US20180290978A1 - Monocarboxylate transport modulators and uses thereof - Google Patents
Monocarboxylate transport modulators and uses thereof Download PDFInfo
- Publication number
- US20180290978A1 US20180290978A1 US15/527,137 US201515527137A US2018290978A1 US 20180290978 A1 US20180290978 A1 US 20180290978A1 US 201515527137 A US201515527137 A US 201515527137A US 2018290978 A1 US2018290978 A1 US 2018290978A1
- Authority
- US
- United States
- Prior art keywords
- nitrogen
- sulfur
- oxygen
- independently selected
- heteroatoms independently
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 59
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 56
- 208000035475 disorder Diseases 0.000 claims abstract description 43
- 201000011510 cancer Diseases 0.000 claims abstract description 33
- -1 substituted-quinolone compounds Chemical class 0.000 claims abstract description 26
- 230000001613 neoplastic effect Effects 0.000 claims abstract description 10
- 230000002159 abnormal effect Effects 0.000 claims abstract description 6
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 6
- 210000000056 organ Anatomy 0.000 claims abstract description 5
- 208000008589 Obesity Diseases 0.000 claims abstract description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 3
- 201000004792 malaria Diseases 0.000 claims abstract description 3
- 235000020824 obesity Nutrition 0.000 claims abstract description 3
- 230000008467 tissue growth Effects 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 93
- 229910052717 sulfur Inorganic materials 0.000 claims description 93
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 90
- 229910052757 nitrogen Inorganic materials 0.000 claims description 85
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 78
- 239000001301 oxygen Chemical group 0.000 claims description 78
- 125000005842 heteroatom Chemical group 0.000 claims description 77
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 76
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 76
- 239000011593 sulfur Chemical group 0.000 claims description 75
- 229920006395 saturated elastomer Polymers 0.000 claims description 72
- 238000000034 method Methods 0.000 claims description 65
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 45
- 239000001257 hydrogen Substances 0.000 claims description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 125000001424 substituent group Chemical group 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
- 150000002367 halogens Chemical group 0.000 claims description 28
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 26
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 25
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 150000002431 hydrogen Chemical group 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 229910020008 S(O) Inorganic materials 0.000 claims description 15
- 102000017298 Monocarboxylate transporters Human genes 0.000 claims description 12
- 108050005244 Monocarboxylate transporters Proteins 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000002619 bicyclic group Chemical group 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 208000030159 metabolic disease Diseases 0.000 claims description 3
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical group C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 229930192474 thiophene Natural products 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 3
- 239000003112 inhibitor Substances 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 208000031229 Cardiomyopathies Diseases 0.000 abstract 1
- 206010016654 Fibrosis Diseases 0.000 abstract 1
- 206010052779 Transplant rejections Diseases 0.000 abstract 1
- 230000004761 fibrosis Effects 0.000 abstract 1
- 230000004962 physiological condition Effects 0.000 abstract 1
- 239000011541 reaction mixture Substances 0.000 description 61
- 239000000203 mixture Substances 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 47
- 210000004027 cell Anatomy 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 239000012043 crude product Substances 0.000 description 34
- 239000000543 intermediate Substances 0.000 description 34
- 239000000243 solution Substances 0.000 description 34
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 28
- 239000012044 organic layer Substances 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 229910052938 sodium sulfate Inorganic materials 0.000 description 27
- 0 BC[W]CC.[1*]C.[2*][Y]C(=C)/C1=C(\[3*])N([4*])C2=C(*=CC=*2)C1=C Chemical compound BC[W]CC.[1*]C.[2*][Y]C(=C)/C1=C(\[3*])N([4*])C2=C(*=CC=*2)C1=C 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000007832 Na2SO4 Substances 0.000 description 22
- 235000019439 ethyl acetate Nutrition 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- 239000012267 brine Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 15
- 201000010099 disease Diseases 0.000 description 14
- VLOYRWBXBBOLJW-UHFFFAOYSA-N ethyl 7-chloro-6-fluoro-4-oxo-1h-quinoline-3-carboxylate Chemical compound ClC1=C(F)C=C2C(=O)C(C(=O)OCC)=CNC2=C1 VLOYRWBXBBOLJW-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 229910052731 fluorine Inorganic materials 0.000 description 13
- 239000001963 growth medium Substances 0.000 description 13
- 125000001072 heteroaryl group Chemical group 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 101000577126 Homo sapiens Monocarboxylate transporter 4 Proteins 0.000 description 12
- 206010025323 Lymphomas Diseases 0.000 description 12
- 102100034068 Monocarboxylate transporter 1 Human genes 0.000 description 12
- 102100025276 Monocarboxylate transporter 4 Human genes 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 12
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 12
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 12
- 206010039491 Sarcoma Diseases 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- MWWATHDPGQKSAR-UHFFFAOYSA-N C#CC Chemical compound C#CC MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
- 208000017604 Hodgkin disease Diseases 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 125000001931 aliphatic group Chemical group 0.000 description 10
- 230000033115 angiogenesis Effects 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- 230000009466 transformation Effects 0.000 description 10
- 208000003174 Brain Neoplasms Diseases 0.000 description 9
- 101000937642 Homo sapiens Malonyl-CoA-acyl carrier protein transacylase, mitochondrial Proteins 0.000 description 9
- 101000590830 Homo sapiens Monocarboxylate transporter 1 Proteins 0.000 description 9
- 101000577129 Homo sapiens Monocarboxylate transporter 5 Proteins 0.000 description 9
- 206010021143 Hypoxia Diseases 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 9
- KGBFKXHEVOTZRK-UHFFFAOYSA-N ethyl 7-chloro-6-fluoro-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylate Chemical compound ClC1=C(F)C=C2C(=O)C(C(=O)OCC)=CN(CC(C)C)C2=C1 KGBFKXHEVOTZRK-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 229910052740 iodine Inorganic materials 0.000 description 9
- 208000032839 leukemia Diseases 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 210000004204 blood vessel Anatomy 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 8
- 230000035935 pregnancy Effects 0.000 description 8
- 238000002953 preparative HPLC Methods 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 230000001154 acute effect Effects 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- QCUVGLQBYVPXDN-UHFFFAOYSA-N diethyl 2-[(3-chloro-4-fluoroanilino)methylidene]propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=CNC1=CC=C(F)C(Cl)=C1 QCUVGLQBYVPXDN-UHFFFAOYSA-N 0.000 description 7
- 230000002496 gastric effect Effects 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 6
- 208000026310 Breast neoplasm Diseases 0.000 description 6
- 201000009030 Carcinoma Diseases 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 206010018338 Glioma Diseases 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 230000001684 chronic effect Effects 0.000 description 6
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 6
- 230000001146 hypoxic effect Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 238000000844 transformation Methods 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- WWGWJLJRSLBGGZ-UHFFFAOYSA-N 7-[(4-chlorophenyl)methyl-methylamino]-6-fluoro-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound ClC1=CC=C(CN(C2=C(C=C3C(C(=CN(C3=C2)CC(C)C)C(=O)O)=O)F)C)C=C1 WWGWJLJRSLBGGZ-UHFFFAOYSA-N 0.000 description 5
- ZHLKDUKUWDDEBO-UHFFFAOYSA-N 7-[benzyl(methyl)amino]-6-fluoro-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound C(C1=CC=CC=C1)N(C1=C(C=C2C(C(=CN(C2=C1)CC(C)C)C(=O)O)=O)F)C ZHLKDUKUWDDEBO-UHFFFAOYSA-N 0.000 description 5
- 102100032412 Basigin Human genes 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 101000798441 Homo sapiens Basigin Proteins 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- 206010027476 Metastases Diseases 0.000 description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 208000011580 syndromic disease Diseases 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- SYCBXSRQZDDVJC-UHFFFAOYSA-N 6-(azetidine-1-carbonyl)-7-[(3,5-dimethylpyrazol-1-yl)methyl]-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound N1(CCC1)C(=O)C=1C=C2C(C(=CN(C2=CC=1CN1N=C(C=C1C)C)CC(C)C)C(=O)O)=O SYCBXSRQZDDVJC-UHFFFAOYSA-N 0.000 description 4
- ILQOGWRYLSERTH-UHFFFAOYSA-N 6-[benzyl(methyl)amino]-7-chloro-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound C(C1=CC=CC=C1)N(C=1C=C2C(C(=CN(C2=CC=1Cl)CC(C)C)C(=O)O)=O)C ILQOGWRYLSERTH-UHFFFAOYSA-N 0.000 description 4
- DHKMQNAPXSRWJQ-UHFFFAOYSA-N 6-fluoro-1-(2-methylpropyl)-7-[methyl(thiophen-2-ylmethyl)amino]-4-oxoquinoline-3-carboxylic acid Chemical compound FC=1C=C2C(C(=CN(C2=CC=1N(CC=1SC=CC=1)C)CC(C)C)C(=O)O)=O DHKMQNAPXSRWJQ-UHFFFAOYSA-N 0.000 description 4
- INMCYOMARTXVMV-UHFFFAOYSA-N 6-fluoro-7-[(3-fluorophenyl)methyl-methylamino]-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound FC=1C=C2C(C(=CN(C2=CC=1N(C)CC1=CC(=CC=C1)F)CC(C)C)C(=O)O)=O INMCYOMARTXVMV-UHFFFAOYSA-N 0.000 description 4
- APIROQHTIMZGOK-UHFFFAOYSA-N 6-fluoro-7-[methyl(pyridin-3-ylmethyl)amino]-4-oxo-1-propan-2-ylquinoline-3-carboxylic acid Chemical compound CC(C)n1cc(C(O)=O)c(=O)c2cc(F)c(cc12)N(C)Cc1cccnc1 APIROQHTIMZGOK-UHFFFAOYSA-N 0.000 description 4
- FTTZDSAAMCPAIA-UHFFFAOYSA-N 7-[benzoyl(methyl)amino]-6-fluoro-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound CN(C(C1=CC=CC=C1)=O)C1=C(C=C2C(C(=CN(C2=C1)CC(C)C)C(=O)O)=O)F FTTZDSAAMCPAIA-UHFFFAOYSA-N 0.000 description 4
- BYPULIYGEXQTEQ-UHFFFAOYSA-N 7-[benzyl(methyl)amino]-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C(C1=CC=CC=C1)N(C1=C(C=C2C(C(=CN(C2=C1)CC)C(=O)O)=O)F)C BYPULIYGEXQTEQ-UHFFFAOYSA-N 0.000 description 4
- 206010003571 Astrocytoma Diseases 0.000 description 4
- 208000021309 Germ cell tumor Diseases 0.000 description 4
- 208000032612 Glial tumor Diseases 0.000 description 4
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 4
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 210000000481 breast Anatomy 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 210000001072 colon Anatomy 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000002267 hypothalamic effect Effects 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000004310 lactic acid Substances 0.000 description 4
- 235000014655 lactic acid Nutrition 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 235000005985 organic acids Nutrition 0.000 description 4
- 201000008968 osteosarcoma Diseases 0.000 description 4
- 230000002611 ovarian Effects 0.000 description 4
- 210000002307 prostate Anatomy 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 201000000849 skin cancer Diseases 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 description 3
- APRZHQXAAWPYHS-UHFFFAOYSA-N 4-[5-[3-(carboxymethoxy)phenyl]-3-(4,5-dimethyl-1,3-thiazol-2-yl)tetrazol-3-ium-2-yl]benzenesulfonate Chemical compound S1C(C)=C(C)N=C1[N+]1=NC(C=2C=C(OCC(O)=O)C=CC=2)=NN1C1=CC=C(S([O-])(=O)=O)C=C1 APRZHQXAAWPYHS-UHFFFAOYSA-N 0.000 description 3
- PLNDBYHZQFQHLR-UHFFFAOYSA-N 6-fluoro-1-(2-methylpropyl)-4-oxo-7-[[3-(trifluoromethyl)phenyl]methylamino]quinoline-3-carboxylic acid Chemical compound FC=1C=C2C(C(=CN(C2=CC=1NCC1=CC(=CC=C1)C(F)(F)F)CC(C)C)C(=O)O)=O PLNDBYHZQFQHLR-UHFFFAOYSA-N 0.000 description 3
- UXWUGOJUOSJYTQ-UHFFFAOYSA-N 6-fluoro-1-(2-methylpropyl)-7-[methyl(1,3-thiazol-5-ylmethyl)amino]-4-oxoquinoline-3-carboxylic acid Chemical compound FC=1C=C2C(C(=CN(C2=CC=1N(CC1=CN=CS1)C)CC(C)C)C(=O)O)=O UXWUGOJUOSJYTQ-UHFFFAOYSA-N 0.000 description 3
- YUNPZCOINKFANM-UHFFFAOYSA-N 6-fluoro-7-[(4-fluorophenyl)methyl-methylamino]-4-oxo-1-propan-2-ylquinoline-3-carboxylic acid Chemical compound FC=1C=C2C(C(=CN(C2=CC=1N(C)CC1=CC=C(C=C1)F)C(C)C)C(=O)O)=O YUNPZCOINKFANM-UHFFFAOYSA-N 0.000 description 3
- VHWHKFFSTAPUDN-UHFFFAOYSA-N 6-fluoro-7-[methyl(1,3-oxazol-5-ylmethyl)amino]-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound FC=1C=C2C(C(=CN(C2=CC=1N(CC1=CN=CO1)C)CC(C)C)C(=O)O)=O VHWHKFFSTAPUDN-UHFFFAOYSA-N 0.000 description 3
- RXDHOZMXSHLCFP-UHFFFAOYSA-N 6-fluoro-7-[methyl(oxan-4-ylmethyl)amino]-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound O1CCC(CC1)CN(C)C1=C(C=C2C(C(=CN(C2=C1)CC(C)C)C(=O)O)=O)F RXDHOZMXSHLCFP-UHFFFAOYSA-N 0.000 description 3
- GSMXVPOJVQIWKG-UHFFFAOYSA-N 6-fluoro-7-[methyl-[(1-methylpiperidin-4-yl)methyl]amino]-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound CN(CC1CCN(CC1)C)C1=C(C=C2C(C(=CN(C2=C1)CC(C)C)C(=O)O)=O)F GSMXVPOJVQIWKG-UHFFFAOYSA-N 0.000 description 3
- ZLSOZRZXLRCANJ-UHFFFAOYSA-N 7-[benzoyl(methyl)amino]-1-benzyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C(C1=CC=CC=C1)N1C=C(C(C2=CC(=C(C=C12)N(C(C1=CC=CC=C1)=O)C)F)=O)C(=O)O ZLSOZRZXLRCANJ-UHFFFAOYSA-N 0.000 description 3
- RRCHTINJSNTGFH-UHFFFAOYSA-N 7-[benzyl(methyl)amino]-6-fluoro-4-oxo-1-propan-2-ylquinoline-3-carboxylic acid Chemical compound C(C1=CC=CC=C1)N(C1=C(C=C2C(C(=CN(C2=C1)C(C)C)C(=O)O)=O)F)C RRCHTINJSNTGFH-UHFFFAOYSA-N 0.000 description 3
- JQPKTBNBYLZZIL-UHFFFAOYSA-N 7-chloro-6-fluoro-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound ClC1=C(C=C2C(C(=CN(C2=C1)CC(C)C)C(=O)O)=O)F JQPKTBNBYLZZIL-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 101000577115 Homo sapiens Monocarboxylate transporter 2 Proteins 0.000 description 3
- 101000577121 Homo sapiens Monocarboxylate transporter 3 Proteins 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 3
- 101710137760 Malonyl-CoA-acyl carrier protein transacylase, mitochondrial Proteins 0.000 description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 3
- 102100025272 Monocarboxylate transporter 2 Human genes 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 208000000453 Skin Neoplasms Diseases 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000011122 anti-angiogenic therapy Methods 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 description 3
- 208000002458 carcinoid tumor Diseases 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 230000019522 cellular metabolic process Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- RHSNBXZAGPQLEA-UHFFFAOYSA-N ethyl 7-chloro-6-fluoro-4-oxo-1-propan-2-ylquinoline-3-carboxylate Chemical compound ClC1=C(F)C=C2C(=O)C(C(=O)OCC)=CN(C(C)C)C2=C1 RHSNBXZAGPQLEA-UHFFFAOYSA-N 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 230000002414 glycolytic effect Effects 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 3
- 210000004153 islets of langerhan Anatomy 0.000 description 3
- 229940116871 l-lactate Drugs 0.000 description 3
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 208000003747 lymphoid leukemia Diseases 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 206010061289 metastatic neoplasm Diseases 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 201000005962 mycosis fungoides Diseases 0.000 description 3
- 201000000050 myeloid neoplasm Diseases 0.000 description 3
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 3
- 230000010627 oxidative phosphorylation Effects 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 230000035790 physiological processes and functions Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 210000004872 soft tissue Anatomy 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 201000008205 supratentorial primitive neuroectodermal tumor Diseases 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 230000004400 visual pathway Effects 0.000 description 3
- 210000000239 visual pathway Anatomy 0.000 description 3
- JVTAAEKCZFNVCJ-UWTATZPHSA-M (R)-lactate Chemical compound C[C@@H](O)C([O-])=O JVTAAEKCZFNVCJ-UWTATZPHSA-M 0.000 description 2
- ZXWCKKSSCIFVBT-UHFFFAOYSA-N 1-(3-fluorophenyl)-n-methylmethanamine Chemical compound CNCC1=CC=CC(F)=C1 ZXWCKKSSCIFVBT-UHFFFAOYSA-N 0.000 description 2
- FIFKRPFWLHBMHL-UHFFFAOYSA-N 1-(3-methoxyphenyl)-n-methylmethanamine Chemical compound CNCC1=CC=CC(OC)=C1 FIFKRPFWLHBMHL-UHFFFAOYSA-N 0.000 description 2
- ALAKRUZUDPXLIG-UHFFFAOYSA-N 2-[benzyl(methyl)amino]-3-chloro-8-oxo-5-propan-2-ylpyrido[2,3-b]pyrazine-7-carboxylic acid Chemical compound C(C1=CC=CC=C1)N(C=1N=C2C(=NC=1Cl)N(C=C(C2=O)C(=O)O)C(C)C)C ALAKRUZUDPXLIG-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- HWGPOUUBUUWURQ-UHFFFAOYSA-N 3-[benzyl(methyl)amino]-2-fluoro-8-oxo-5-propan-2-ylpyrido[2,3-b]pyrazine-7-carboxylic acid Chemical compound C(C1=CC=CC=C1)N(C1=C(N=C2C(=N1)N(C=C(C2=O)C(=O)O)C(C)C)F)C HWGPOUUBUUWURQ-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- CHXBKRWDPGBEIL-UHFFFAOYSA-N 6-(azetidine-1-carbonyl)-7-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound N1(CCC1)C(=O)C=1C=C2C(C(=CN(C2=CC=1CC=1C(=NNC=1C)C)CC(C)C)C(=O)O)=O CHXBKRWDPGBEIL-UHFFFAOYSA-N 0.000 description 2
- OCKUPUVNEKQGJP-UHFFFAOYSA-N 6-(azetidine-1-carbonyl)-7-[benzyl(methyl)amino]-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound N1(CCC1)C(=O)C=1C=C2C(C(=CN(C2=CC=1N(C)CC1=CC=CC=C1)CC(C)C)C(=O)O)=O OCKUPUVNEKQGJP-UHFFFAOYSA-N 0.000 description 2
- FEORZGHNTMOSDU-UHFFFAOYSA-N 6-[benzyl(methyl)amino]-7-fluoro-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound C(C1=CC=CC=C1)N(C=1C=C2C(C(=CN(C2=CC=1F)CC(C)C)C(=O)O)=O)C FEORZGHNTMOSDU-UHFFFAOYSA-N 0.000 description 2
- DDZACRBICAAQPB-UHFFFAOYSA-N 6-fluoro-1-(2-methylpropyl)-7-[methyl-[[3-(trifluoromethyl)phenyl]methyl]amino]-4-oxoquinoline-3-carboxylic acid Chemical compound FC=1C=C2C(C(=CN(C2=CC=1N(CC1=CC(=CC=C1)C(F)(F)F)C)CC(C)C)C(=O)O)=O DDZACRBICAAQPB-UHFFFAOYSA-N 0.000 description 2
- QBUWCHVHQWRCDT-UHFFFAOYSA-N 6-fluoro-7-[(3-methoxyphenyl)methyl-methylamino]-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound COC=1C=C(CN(C)C2=C(C=C3C(C(=CN(C3=C2)CC(C)C)C(=O)O)=O)F)C=CC=1 QBUWCHVHQWRCDT-UHFFFAOYSA-N 0.000 description 2
- DRNUWBNZWMUTKU-UHFFFAOYSA-N 7-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-6-fluoro-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound CC1=NNC(=C1CC1=C(C=C2C(C(=CN(C2=C1)CC(C)C)C(=O)O)=O)F)C DRNUWBNZWMUTKU-UHFFFAOYSA-N 0.000 description 2
- QUGQYENVLGBBGI-UHFFFAOYSA-N 7-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-6-fluoro-4-oxo-1-propan-2-ylquinoline-3-carboxylic acid Chemical compound CC1=NNC(=C1CC1=C(C=C2C(C(=CN(C2=C1)C(C)C)C(=O)O)=O)F)C QUGQYENVLGBBGI-UHFFFAOYSA-N 0.000 description 2
- NQZISIIZVOQQPE-UHFFFAOYSA-N 7-[(4-chlorophenyl)methyl-methylamino]-6-fluoro-4-oxo-1-propan-2-ylquinoline-3-carboxylic acid Chemical compound ClC1=CC=C(CN(C2=C(C=C3C(C(=CN(C3=C2)C(C)C)C(=O)O)=O)F)C)C=C1 NQZISIIZVOQQPE-UHFFFAOYSA-N 0.000 description 2
- LIHPIQFWRNGEFC-UHFFFAOYSA-N 7-[benzoyl(methyl)amino]-6-fluoro-4-oxo-1-(pyridin-3-ylmethyl)quinoline-3-carboxylic acid Chemical compound FC=1C=C2C(C(=CN(C2=CC=1N(C(C1=CC=CC=C1)=O)C)CC=1C=NC=CC=1)C(=O)O)=O LIHPIQFWRNGEFC-UHFFFAOYSA-N 0.000 description 2
- HMAROBWDSIGFQS-UHFFFAOYSA-N 7-[benzyl(methyl)amino]-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound C(C1=CC=CC=C1)N(C1=CC=C2C(C(=CN(C2=C1)CC(C)C)C(=O)O)=O)C HMAROBWDSIGFQS-UHFFFAOYSA-N 0.000 description 2
- WGLSDUHZYGZCKS-UHFFFAOYSA-N 7-[benzyl(methyl)amino]-6-cyano-4-oxo-1-propan-2-ylquinoline-3-carboxylic acid Chemical compound C(C1=CC=CC=C1)N(C1=C(C=C2C(C(=CN(C2=C1)C(C)C)C(=O)O)=O)C#N)C WGLSDUHZYGZCKS-UHFFFAOYSA-N 0.000 description 2
- VKACCTLCXUHCNG-UHFFFAOYSA-N 7-[cyclohexylmethyl(methyl)amino]-6-fluoro-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1(CCCCC1)CN(C1=C(C=C2C(C(=CN(C2=C1)CC(C)C)C(=O)O)=O)F)C VKACCTLCXUHCNG-UHFFFAOYSA-N 0.000 description 2
- GBRHQMDODCICAI-UHFFFAOYSA-N 7-chloro-6-fluoro-4-oxo-1-propan-2-ylquinoline-3-carboxylic acid Chemical compound FC1=C(Cl)C=C2N(C(C)C)C=C(C(O)=O)C(=O)C2=C1 GBRHQMDODCICAI-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010060971 Astrocytoma malignant Diseases 0.000 description 2
- 102000015279 Basigin Human genes 0.000 description 2
- 108010064528 Basigin Proteins 0.000 description 2
- 206010004593 Bile duct cancer Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 206010006143 Brain stem glioma Diseases 0.000 description 2
- SCHBLMGZRACFIM-UHFFFAOYSA-N CC(C)(C)C1=CC=C(Cl)C=C1.CC(C)(C)C1=CC=CC=C1.CC1=CC=CC(C(C)(C)C)=C1 Chemical compound CC(C)(C)C1=CC=C(Cl)C=C1.CC(C)(C)C1=CC=CC=C1.CC1=CC=CC(C(C)(C)C)=C1 SCHBLMGZRACFIM-UHFFFAOYSA-N 0.000 description 2
- CMOYPPBKFKPVEH-UHFFFAOYSA-N CC(C)(C)C1CC1.CC(C)C(C)(C)C.CC(C)CC(C)(C)C Chemical compound CC(C)(C)C1CC1.CC(C)C(C)(C)C.CC(C)CC(C)(C)C CMOYPPBKFKPVEH-UHFFFAOYSA-N 0.000 description 2
- QKNXWYPMRGIXNW-UHFFFAOYSA-N CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=N2 Chemical compound CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=N2 QKNXWYPMRGIXNW-UHFFFAOYSA-N 0.000 description 2
- HXLNUWSRUYHFII-UHFFFAOYSA-N CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1 Chemical compound CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1 HXLNUWSRUYHFII-UHFFFAOYSA-N 0.000 description 2
- 206010007275 Carcinoid tumour Diseases 0.000 description 2
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 206010014967 Ependymoma Diseases 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000012468 Ewing sarcoma/peripheral primitive neuroectodermal tumor Diseases 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010061252 Intraocular melanoma Diseases 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- 206010023825 Laryngeal cancer Diseases 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 206010025557 Malignant fibrous histiocytoma of bone Diseases 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 208000000172 Medulloblastoma Diseases 0.000 description 2
- 108010006519 Molecular Chaperones Proteins 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 108010039918 Polylysine Proteins 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 201000000582 Retinoblastoma Diseases 0.000 description 2
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 2
- 206010061934 Salivary gland cancer Diseases 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 201000009365 Thymic carcinoma Diseases 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 201000005969 Uveal melanoma Diseases 0.000 description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 2
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 2
- 230000006536 aerobic glycolysis Effects 0.000 description 2
- 206010064930 age-related macular degeneration Diseases 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 201000007335 cerebellar astrocytoma Diseases 0.000 description 2
- 208000030239 cerebral astrocytoma Diseases 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 208000024519 eye neoplasm Diseases 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 208000029824 high grade glioma Diseases 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 210000000244 kidney pelvis Anatomy 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 150000003893 lactate salts Chemical class 0.000 description 2
- 206010023841 laryngeal neoplasm Diseases 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 208000030883 malignant astrocytoma Diseases 0.000 description 2
- 201000011614 malignant glioma Diseases 0.000 description 2
- 208000006178 malignant mesothelioma Diseases 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 208000018795 nasal cavity and paranasal sinus carcinoma Diseases 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 201000008106 ocular cancer Diseases 0.000 description 2
- 201000002575 ocular melanoma Diseases 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 150000003901 oxalic acid esters Chemical class 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 208000010626 plasma cell neoplasm Diseases 0.000 description 2
- 229920000656 polylysine Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 2
- 229940076788 pyruvate Drugs 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 206010044412 transitional cell carcinoma Diseases 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 208000018417 undifferentiated high grade pleomorphic sarcoma of bone Diseases 0.000 description 2
- 210000000626 ureter Anatomy 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LMBUJNXYGGNSAH-UHFFFAOYSA-N 1-(4-chlorophenyl)-n-methylmethanamine Chemical compound CNCC1=CC=C(Cl)C=C1 LMBUJNXYGGNSAH-UHFFFAOYSA-N 0.000 description 1
- SZJIQLSCDIEJFC-UHFFFAOYSA-N 1-(4-fluorophenyl)-n-methylmethanamine Chemical compound CNCC1=CC=C(F)C=C1 SZJIQLSCDIEJFC-UHFFFAOYSA-N 0.000 description 1
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- KSZUVEGORKZMFV-UHFFFAOYSA-N 1-benzyl-6-fluoro-7-[(3-methoxyphenyl)methyl-methylamino]-4-oxoquinoline-3-carboxylic acid Chemical compound COC=1C=C(CN(C)C2=C(C=C3C(C(=CN(C3=C2)CC2=CC=CC=C2)C(=O)O)=O)F)C=CC=1 KSZUVEGORKZMFV-UHFFFAOYSA-N 0.000 description 1
- WZWFUSKOYHUXNG-UHFFFAOYSA-N 1-benzyl-7-chloro-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1CC1=CC=CC=C1 WZWFUSKOYHUXNG-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- GBCQLGDTLMHVHU-UHFFFAOYSA-N 2,3,4,4a,5,6,7,8,9,9a-decahydro-1h-benzo[7]annulene Chemical compound C1CCCCC2CCCCC21 GBCQLGDTLMHVHU-UHFFFAOYSA-N 0.000 description 1
- OIPKZAXCUMFSTA-UHFFFAOYSA-N 2,5-dimethyl-1,3-dihydropyrazole Chemical compound CN1CC=C(C)N1 OIPKZAXCUMFSTA-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical group C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- XXXOBNJIIZQSPT-UHFFFAOYSA-N 2-methyl-4-nitrobenzoic acid Chemical compound CC1=CC([N+]([O-])=O)=CC=C1C(O)=O XXXOBNJIIZQSPT-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- SDXAWLJRERMRKF-UHFFFAOYSA-N 3,5-dimethyl-1h-pyrazole Chemical compound CC=1C=C(C)NN=1 SDXAWLJRERMRKF-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- ILNJBIQQAIIMEY-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CN=C21 ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 description 1
- RZTOVXLRGWFECB-UHFFFAOYSA-N 6-(azetidine-1-carbonyl)-1-(2-methylpropyl)-4-oxo-7-[[2-(trifluoromethyl)phenyl]methyl]quinoline-3-carboxylic acid Chemical compound N1(CCC1)C(=O)C=1C=C2C(C(=CN(C2=CC=1CC1=C(C=CC=C1)C(F)(F)F)CC(C)C)C(=O)O)=O RZTOVXLRGWFECB-UHFFFAOYSA-N 0.000 description 1
- DYVOUPIEKJTCFK-UHFFFAOYSA-N 6-(azetidine-1-carbonyl)-1-cyclopropyl-4-oxo-7-[[2-(trifluoromethyl)phenyl]methyl]quinoline-3-carboxylic acid Chemical compound N1(CCC1)C(=O)C=1C=C2C(C(=CN(C2=CC=1CC1=C(C=CC=C1)C(F)(F)F)C1CC1)C(=O)O)=O DYVOUPIEKJTCFK-UHFFFAOYSA-N 0.000 description 1
- MRCIFITXYUUIGQ-UHFFFAOYSA-N 6-(azetidine-1-carbonyl)-4-oxo-1-propan-2-yl-7-[[2-(trifluoromethyl)phenyl]methyl]quinoline-3-carboxylic acid Chemical compound N1(CCC1)C(=O)C=1C=C2C(C(=CN(C2=CC=1CC1=C(C=CC=C1)C(F)(F)F)C(C)C)C(=O)O)=O MRCIFITXYUUIGQ-UHFFFAOYSA-N 0.000 description 1
- HRRGCEMGFQBRMT-UHFFFAOYSA-N 6-cyano-7-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-oxo-1-propan-2-ylquinoline-3-carboxylic acid Chemical compound C(#N)C=1C=C2C(C(=CN(C2=CC=1CC=1C(=NNC=1C)C)C(C)C)C(=O)O)=O HRRGCEMGFQBRMT-UHFFFAOYSA-N 0.000 description 1
- IIPQWJNRRCXYDQ-UHFFFAOYSA-N 6-fluoro-1-(2-methylpropyl)-4-oxo-7-[[2-(trifluoromethyl)phenyl]methyl]quinoline-3-carboxylic acid Chemical compound FC=1C=C2C(C(=CN(C2=CC=1CC1=C(C=CC=C1)C(F)(F)F)CC(C)C)C(=O)O)=O IIPQWJNRRCXYDQ-UHFFFAOYSA-N 0.000 description 1
- JBBXGRRXMLRKTG-UHFFFAOYSA-N 6-fluoro-4-oxo-1-propan-2-yl-7-[[2-(trifluoromethyl)phenyl]methyl]quinoline-3-carboxylic acid Chemical compound FC=1C=C2C(C(=CN(C2=CC=1CC1=C(C=CC=C1)C(F)(F)F)C(C)C)C(=O)O)=O JBBXGRRXMLRKTG-UHFFFAOYSA-N 0.000 description 1
- VRQJKVPOGSEMNF-UHFFFAOYSA-N 6-fluoro-7-(methylamino)-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid Chemical compound FC=1C=C2C(C(=CN(C2=CC=1NC)CC(C)C)C(=O)O)=O VRQJKVPOGSEMNF-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- JRALEQJMJHMLRR-UHFFFAOYSA-N 7-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-oxo-1-propan-2-yl-6-(trifluoromethyl)quinoline-3-carboxylic acid Chemical compound CC1=NNC(=C1CC1=C(C=C2C(C(=CN(C2=C1)C(C)C)C(=O)O)=O)C(F)(F)F)C JRALEQJMJHMLRR-UHFFFAOYSA-N 0.000 description 1
- SAURAEREDCRPOP-UHFFFAOYSA-N 7-[(3,5-dimethylpyrazol-1-yl)methyl]-3-ethoxycarbonyl-1-(2-methylpropyl)-4-oxoquinoline-6-carboxylic acid Chemical compound CC1=NN(C(=C1)C)CC1=C(C=C2C(C(=CN(C2=C1)CC(C)C)C(=O)OCC)=O)C(=O)O SAURAEREDCRPOP-UHFFFAOYSA-N 0.000 description 1
- HDJVUHMWQXSCTR-UHFFFAOYSA-N 7-[benzyl(methyl)amino]-4-oxo-1-propan-2-yl-6-(trifluoromethyl)quinoline-3-carboxylic acid Chemical compound C(C1=CC=CC=C1)N(C1=C(C=C2C(C(=CN(C2=C1)C(C)C)C(=O)O)=O)C(F)(F)F)C HDJVUHMWQXSCTR-UHFFFAOYSA-N 0.000 description 1
- WGCDZZLWTWTNLR-UHFFFAOYSA-N 7-[benzyl(methyl)amino]-6-fluoro-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylic acid 7-[benzyl(methyl)amino]-6-fluoro-4-oxo-1-propan-2-ylquinoline-3-carboxylic acid Chemical compound CC(C)n1cc(C(O)=O)c(=O)c2cc(F)c(cc12)N(C)Cc1ccccc1.CC(C)Cn1cc(C(O)=O)c(=O)c2cc(F)c(cc12)N(C)Cc1ccccc1 WGCDZZLWTWTNLR-UHFFFAOYSA-N 0.000 description 1
- WNNSMMJBBOPPOT-UHFFFAOYSA-N 7-chloro-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound FC1=C(Cl)C=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 WNNSMMJBBOPPOT-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 208000002008 AIDS-Related Lymphoma Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 102000009840 Angiopoietins Human genes 0.000 description 1
- 108010009906 Angiopoietins Proteins 0.000 description 1
- 102000012936 Angiostatins Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- HEKBSWREESJSHT-DWWUPETLSA-J B=S(C)(=N)/N=B/[AlH](Cl)(Cl)(Cl)Cl.C1=CC=C(OC2=CC=CC=C2)C=C1.CC(C)CBr.CC1=CC(C)=NC1.CC1=CC(C)=NN1CC1=CC2=C(C=C1C(=O)N1CCC1)C(=O)C(C(=O)O)=CN2CC(C)C.CC1=CC([N+](=O)[O-])=CC=C1C(=O)O.CCO/C=C(/C(C)=O)C(=O)OCC.CCOC(=O)C(=CNC1=CC=C(C(=O)OC)C(CN2N=C(C)C=C2C)=C1)C(=O)OCC.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)N3CCC3)C(CN3N=C(C)C=C3C)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)O)C(CN3N=C(C)C=C3C)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)OC)C(CN3N=C(C)C=C3C)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(C(=O)OC)C(CN3N=C(C)C=C3C)=C2)C1=O.CO.COC(=O)C1=CC=C(N)C=C1CN1N=C(C)C=C1C.COC(=O)C1=CC=C([N+](=O)[O-])C=C1C.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CBr.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CN1N=C(C)C=C1C Chemical compound B=S(C)(=N)/N=B/[AlH](Cl)(Cl)(Cl)Cl.C1=CC=C(OC2=CC=CC=C2)C=C1.CC(C)CBr.CC1=CC(C)=NC1.CC1=CC(C)=NN1CC1=CC2=C(C=C1C(=O)N1CCC1)C(=O)C(C(=O)O)=CN2CC(C)C.CC1=CC([N+](=O)[O-])=CC=C1C(=O)O.CCO/C=C(/C(C)=O)C(=O)OCC.CCOC(=O)C(=CNC1=CC=C(C(=O)OC)C(CN2N=C(C)C=C2C)=C1)C(=O)OCC.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)N3CCC3)C(CN3N=C(C)C=C3C)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)O)C(CN3N=C(C)C=C3C)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)OC)C(CN3N=C(C)C=C3C)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(C(=O)OC)C(CN3N=C(C)C=C3C)=C2)C1=O.CO.COC(=O)C1=CC=C(N)C=C1CN1N=C(C)C=C1C.COC(=O)C1=CC=C([N+](=O)[O-])C=C1C.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CBr.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CN1N=C(C)C=C1C HEKBSWREESJSHT-DWWUPETLSA-J 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 102000036365 BRCA1 Human genes 0.000 description 1
- 108700020463 BRCA1 Proteins 0.000 description 1
- 101150072950 BRCA1 gene Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- JEVPBAXZDLLTHY-UHFFFAOYSA-N BrCC1=CC=CC=C1.CCOC(=O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O Chemical compound BrCC1=CC=CC=C1.CCOC(=O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O JEVPBAXZDLLTHY-UHFFFAOYSA-N 0.000 description 1
- JXHUGJQOXVQDDG-UHFFFAOYSA-N BrCC1=CC=CC=C1.CCOC(=O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O.CNCC1=CC(OC)=CC=C1.COC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC2=CC=CC=C2)=C1.O=C(O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O Chemical compound BrCC1=CC=CC=C1.CCOC(=O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O.CNCC1=CC(OC)=CC=C1.COC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC2=CC=CC=C2)=C1.O=C(O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O JXHUGJQOXVQDDG-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- YTCLRLSURFYEBZ-UHFFFAOYSA-N C.CC1=CC(C)=NN1CC1=CC2=C(C=C1C(=O)N1CCC1)C(=O)C(C(=O)O)=CN2CC(C)C.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)N3CCC3)C(CN3N=C(C)C=C3C)=C2)C1=O Chemical compound C.CC1=CC(C)=NN1CC1=CC2=C(C=C1C(=O)N1CCC1)C(=O)C(C(=O)O)=CN2CC(C)C.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)N3CCC3)C(CN3N=C(C)C=C3C)=C2)C1=O YTCLRLSURFYEBZ-UHFFFAOYSA-N 0.000 description 1
- ATQFBOKBZIFSHN-UHFFFAOYSA-N C.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)N3CCC3)C(CN3N=C(C)C=C3C)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)O)C(CN3N=C(C)C=C3C)=C2)C1=O Chemical compound C.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)N3CCC3)C(CN3N=C(C)C=C3C)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)O)C(CN3N=C(C)C=C3C)=C2)C1=O ATQFBOKBZIFSHN-UHFFFAOYSA-N 0.000 description 1
- NSASCBQLCXFXNC-UHFFFAOYSA-N C.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)O)C(CN3N=C(C)C=C3C)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)OC)C(CN3N=C(C)C=C3C)=C2)C1=O Chemical compound C.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)O)C(CN3N=C(C)C=C3C)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(C(=O)OC)C(CN3N=C(C)C=C3C)=C2)C1=O NSASCBQLCXFXNC-UHFFFAOYSA-N 0.000 description 1
- PEVBEPJUWHNWKN-DEPKBADVSA-N C1=CC=C(OC2=CC=CC=C2)C=C1.CC(C)Br.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CN=C1)C(F)=C2.CCO/C=C(/C(C)=O)C(=O)OCC.CCOC(=O)C(=CNC1=CC=C(F)C(Cl)=C1)C(=O)OCC.CCOC(=O)C1=CN(C(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O.CNCC1=CN=CC=C1.NC1=CC=C(F)C(Cl)=C1 Chemical compound C1=CC=C(OC2=CC=CC=C2)C=C1.CC(C)Br.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CN=C1)C(F)=C2.CCO/C=C(/C(C)=O)C(=O)OCC.CCOC(=O)C(=CNC1=CC=C(F)C(Cl)=C1)C(=O)OCC.CCOC(=O)C1=CN(C(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O.CNCC1=CN=CC=C1.NC1=CC=C(F)C(Cl)=C1 PEVBEPJUWHNWKN-DEPKBADVSA-N 0.000 description 1
- GUILYESGQYQERH-BQEYVCFFSA-N C1=CC=C(OC2=CC=CC=C2)C=C1.CC(C)CBr.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(N(C)CC1=CC=CC=C1)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CCO/C=C(/C(C)=O)C(=O)OCC.CCOC(=O)C(=CNC1=CC=C(F)C(Cl)=C1)C(=O)OCC.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O.CNCC1=CC=CC=C1.NC1=CC=C(F)C(Cl)=C1 Chemical compound C1=CC=C(OC2=CC=CC=C2)C=C1.CC(C)CBr.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(N(C)CC1=CC=CC=C1)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CCO/C=C(/C(C)=O)C(=O)OCC.CCOC(=O)C(=CNC1=CC=C(F)C(Cl)=C1)C(=O)OCC.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O.CNCC1=CC=CC=C1.NC1=CC=C(F)C(Cl)=C1 GUILYESGQYQERH-BQEYVCFFSA-N 0.000 description 1
- GECAATAEGSFVOU-UHFFFAOYSA-N C1=CC=C(OC2=CC=CC=C2)C=C1.CCOC(=O)C(=CNC1=CC=C(C(=O)OC)C(CN2N=C(C)C=C2C)=C1)C(=O)OCC.CCOC(=O)C1=CNC2=C(C=C(C(=O)OC)C(CN3N=C(C)C=C3C)=C2)C1=O Chemical compound C1=CC=C(OC2=CC=CC=C2)C=C1.CCOC(=O)C(=CNC1=CC=C(C(=O)OC)C(CN2N=C(C)C=C2C)=C1)C(=O)OCC.CCOC(=O)C1=CNC2=C(C=C(C(=O)OC)C(CN3N=C(C)C=C3C)=C2)C1=O GECAATAEGSFVOU-UHFFFAOYSA-N 0.000 description 1
- PWQDUGCYCPSKGV-UHFFFAOYSA-N C1=CC=C(OC2=CC=CC=C2)C=C1.CCOC(=O)C(=CNC1=CC=C(F)C(Cl)=C1)C(=O)OCC.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O Chemical compound C1=CC=C(OC2=CC=CC=C2)C=C1.CCOC(=O)C(=CNC1=CC=C(F)C(Cl)=C1)C(=O)OCC.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O PWQDUGCYCPSKGV-UHFFFAOYSA-N 0.000 description 1
- WWZQQBYECMJHLZ-UHFFFAOYSA-N CC(C)(C)c(cc1)cc(CC(C)(C)c2cccc(C(F)(F)F)c2)c1Cl Chemical compound CC(C)(C)c(cc1)cc(CC(C)(C)c2cccc(C(F)(F)F)c2)c1Cl WWZQQBYECMJHLZ-UHFFFAOYSA-N 0.000 description 1
- YGUJVXVLTSBCTP-UHFFFAOYSA-N CC(C)Br.CCOC(=O)C1=CN(C(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O Chemical compound CC(C)Br.CCOC(=O)C1=CN(C(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O YGUJVXVLTSBCTP-UHFFFAOYSA-N 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N CC(C)C(N)=O Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- UCDHFULAHLZERR-UHFFFAOYSA-N CC(C)CBr.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O Chemical compound CC(C)CBr.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O UCDHFULAHLZERR-UHFFFAOYSA-N 0.000 description 1
- VNFPAZOOTXOAKB-UHFFFAOYSA-N CC(C)CN(C=C(C(O)=O)C(c1c2)=O)c1cc(N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c2F Chemical compound CC(C)CN(C=C(C(O)=O)C(c1c2)=O)c1cc(N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c2F VNFPAZOOTXOAKB-UHFFFAOYSA-N 0.000 description 1
- YKMLDVRUVKCAIG-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(N(C)CC1=CC=CC=C1)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CNCC1=CC=CC=C1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(N(C)CC1=CC=CC=C1)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CNCC1=CC=CC=C1 YKMLDVRUVKCAIG-UHFFFAOYSA-N 0.000 description 1
- KDWPXCYZAMXJGC-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)C(=O)C1=CC=CC=C1)C(F)=C2.CN.CNC1=CC2=C(C=C1F)C(=O)C(C(=O)O)=CN2CC(C)C.O=C(Cl)C1=CC=CC=C1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)C(=O)C1=CC=CC=C1)C(F)=C2.CN.CNC1=CC2=C(C=C1F)C(=O)C(C(=O)O)=CN2CC(C)C.O=C(Cl)C1=CC=CC=C1 KDWPXCYZAMXJGC-UHFFFAOYSA-N 0.000 description 1
- FABKKWIOPYGXLM-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC(F)=CC=C1)C(F)=C2.CNCC1=CC(F)=CC=C1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC(F)=CC=C1)C(F)=C2.CNCC1=CC(F)=CC=C1 FABKKWIOPYGXLM-UHFFFAOYSA-N 0.000 description 1
- BIKSXNHJFGHSFC-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=C(Cl)C=C1)C(F)=C2.CNCC1=CC=C(Cl)C=C1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=C(Cl)C=C1)C(F)=C2.CNCC1=CC=C(Cl)C=C1 BIKSXNHJFGHSFC-UHFFFAOYSA-N 0.000 description 1
- MGADBHYYYNMJEN-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1CCN(C)CC1)C(F)=C2.CNCC1CCN(C)CC1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1CCN(C)CC1)C(F)=C2.CNCC1CCN(C)CC1 MGADBHYYYNMJEN-UHFFFAOYSA-N 0.000 description 1
- GFUYQZURGPBBMX-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1CCOCC1)C(F)=C2.CNCC1CCOCC1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1CCOCC1)C(F)=C2.CNCC1CCOCC1 GFUYQZURGPBBMX-UHFFFAOYSA-N 0.000 description 1
- PCYASYFGJRBXLO-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC1=CC(CN)=CC=C1.CC1=CC=CC(CNC2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC1=CC(CN)=CC=C1.CC1=CC=CC(CNC2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1 PCYASYFGJRBXLO-UHFFFAOYSA-N 0.000 description 1
- PZMVVBJHCCCJIT-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1.CNCC1=CC(OC)=CC=C1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1.CNCC1=CC(OC)=CC=C1 PZMVVBJHCCCJIT-UHFFFAOYSA-N 0.000 description 1
- NGWCNJBRKCQFAJ-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1.CNCC1=CC=CC(C)=C1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1.CNCC1=CC=CC(C)=C1 NGWCNJBRKCQFAJ-UHFFFAOYSA-N 0.000 description 1
- JCPMXEXETSOFSH-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O JCPMXEXETSOFSH-UHFFFAOYSA-N 0.000 description 1
- KJCNWWRWOXGTDI-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CN.CNC1=CC2=C(C=C1F)C(=O)C(C(=O)O)=CN2CC(C)C Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CN.CNC1=CC2=C(C=C1F)C(=O)C(C(=O)O)=CN2CC(C)C KJCNWWRWOXGTDI-UHFFFAOYSA-N 0.000 description 1
- UFMLFNXTLUQZLP-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)C(=O)C1=CC=CC=C1)C(F)=C2.CN(C(=O)C1=CC=CC=C1)C1=CC2=C(C=C1F)C(=O)C(C(=O)O)=CN2CC1=CC=CC=C1.CN(C(=O)C1=CC=CC=C1)C1=CC2=C(C=C1F)C(=O)C(C(=O)O)=CN2CC1=CC=CN=C1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)C(=O)C1=CC=CC=C1)C(F)=C2.CN(C(=O)C1=CC=CC=C1)C1=CC2=C(C=C1F)C(=O)C(C(=O)O)=CN2CC1=CC=CC=C1.CN(C(=O)C1=CC=CC=C1)C1=CC2=C(C=C1F)C(=O)C(C(=O)O)=CN2CC1=CC=CN=C1 UFMLFNXTLUQZLP-UHFFFAOYSA-N 0.000 description 1
- MVDQISSFKXLIQJ-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)C(=O)C1=CC=CC=C1)C(F)=C2.CNC1=CC2=C(C=C1F)C(=O)C(C(=O)O)=CN2CC(C)C.O=C(Cl)C1=CC=CC=C1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)C(=O)C1=CC=CC=C1)C(F)=C2.CNC1=CC2=C(C=C1F)C(=O)C(C(=O)O)=CN2CC(C)C.O=C(Cl)C1=CC=CC=C1 MVDQISSFKXLIQJ-UHFFFAOYSA-N 0.000 description 1
- JFLVMLWRUDZYTC-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=C([Cl])C=C1)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CS1)C(F)=C2.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC2=CC=CC=C2)=C1.CC1=CC=CC(CNC2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=C([Cl])C=C1)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CS1)C(F)=C2.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC2=CC=CC=C2)=C1.CC1=CC=CC(CNC2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1 JFLVMLWRUDZYTC-UHFFFAOYSA-N 0.000 description 1
- LOEGBXYKTLSUCD-RWQGSHLVSA-M CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CS1)C(F)=C2.CCOC(=O)C(/C=N/C1=CC=C(F)C(Br)=C1)C(=O)OCC.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Br)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(N(C)CC3=CC=CS3)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Br)=C2)C1=O.CCOC=C(C(=O)OCC)C(=O)OCC.CNCC1=CC=CS1.NC1=CC=C(F)C(Br)=C1.O[Na] Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CS1)C(F)=C2.CCOC(=O)C(/C=N/C1=CC=C(F)C(Br)=C1)C(=O)OCC.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Br)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(N(C)CC3=CC=CS3)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Br)=C2)C1=O.CCOC=C(C(=O)OCC)C(=O)OCC.CNCC1=CC=CS1.NC1=CC=C(F)C(Br)=C1.O[Na] LOEGBXYKTLSUCD-RWQGSHLVSA-M 0.000 description 1
- RNQZSJMOPCIRMF-UHFFFAOYSA-M CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CS1)C(F)=C2.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(N(C)CC3=CC=CS3)=C2)C1=O.O[Na] Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CS1)C(F)=C2.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(N(C)CC3=CC=CS3)=C2)C1=O.O[Na] RNQZSJMOPCIRMF-UHFFFAOYSA-M 0.000 description 1
- YYXZMLVKRNSMTI-UHFFFAOYSA-N CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1CCCCC1)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1CCN(C)CC1)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1CCOCC1)C(F)=C2 Chemical compound CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1CCCCC1)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1CCN(C)CC1)C(F)=C2.CC(C)CN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1CCOCC1)C(F)=C2 YYXZMLVKRNSMTI-UHFFFAOYSA-N 0.000 description 1
- GRHOOBIELYZBCM-UHFFFAOYSA-N CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=C(F)C=C1)C(F)=C2.CNCC1=CC=C(F)C=C1 Chemical compound CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=C(F)C=C1)C(F)=C2.CNCC1=CC=C(F)C=C1 GRHOOBIELYZBCM-UHFFFAOYSA-N 0.000 description 1
- BEZOZVUHOAABJZ-UHFFFAOYSA-N CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CNCC1=CC=CC=C1 Chemical compound CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CNCC1=CC=CC=C1 BEZOZVUHOAABJZ-UHFFFAOYSA-N 0.000 description 1
- FHMDQIRHCDZKCH-UHFFFAOYSA-N CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CN=C1)C(F)=C2.CNCC1=CN=CC=C1 Chemical compound CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CN=C1)C(F)=C2.CNCC1=CN=CC=C1 FHMDQIRHCDZKCH-UHFFFAOYSA-N 0.000 description 1
- DNDRICDPDBHJNG-UHFFFAOYSA-N CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CCOC(=O)C1=CN(C(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O Chemical compound CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CCOC(=O)C1=CN(C(C)C)C2=C(C=C(F)C(Cl)=C2)C1=O DNDRICDPDBHJNG-UHFFFAOYSA-N 0.000 description 1
- FIPMUWISQCXSDR-UHFFFAOYSA-N CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(N(C)CC1=CC=CC=C1)=N2 Chemical compound CC(C)N1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(N(C)CC1=CC=CC=C1)=N2 FIPMUWISQCXSDR-UHFFFAOYSA-N 0.000 description 1
- PJUFVHCIYRQXJD-UHFFFAOYSA-N CC(C)N1C=C(C(=O)O)C(=O)C2=C1N=C(Cl)C(N(C)CC1=CC=CC=C1)=C2 Chemical compound CC(C)N1C=C(C(=O)O)C(=O)C2=C1N=C(Cl)C(N(C)CC1=CC=CC=C1)=C2 PJUFVHCIYRQXJD-UHFFFAOYSA-N 0.000 description 1
- NMJIZJCOTUVMNE-UHFFFAOYSA-N CC(C)N1C=C(C(=O)O)C(=O)C2=C1N=C(N(C)CC1=CC=CC=C1)C(F)=C2 Chemical compound CC(C)N1C=C(C(=O)O)C(=O)C2=C1N=C(N(C)CC1=CC=CC=C1)C(F)=C2 NMJIZJCOTUVMNE-UHFFFAOYSA-N 0.000 description 1
- GTUVEJIJAPEHPW-UHFFFAOYSA-N CC1=C(C(C)(C)C)C=CC=C1.CC1=CC(C)=NN1C(C)(C)C.CC1=NNC(C)=C1C(C)(C)C.CC1=NNC(C)=C1C(C)(C)C Chemical compound CC1=C(C(C)(C)C)C=CC=C1.CC1=CC(C)=NN1C(C)(C)C.CC1=NNC(C)=C1C(C)(C)C.CC1=NNC(C)=C1C(C)(C)C GTUVEJIJAPEHPW-UHFFFAOYSA-N 0.000 description 1
- YNLWJOALGHYDIS-UHFFFAOYSA-N CC1=C(CC2=CC3=C(C=C2C(=O)N2CCC2)C(=O)C(C(=O)O)=CN3C(C)C)C=CC=C1.CC1=C(CC2=CC3=C(C=C2C(=O)N2CCC2)C(=O)C(C(=O)O)=CN3C2CC2)C=CC=C1.CC1=C(CC2=CC3=C(C=C2C(=O)N2CCC2)C(=O)C(C(=O)O)=CN3CC(C)C)C=CC=C1.CC1=CC(C)=NN1CC1=CC2=C(C=C1C(=O)N1CCC1)C(=O)C(C(=O)O)=CN2CC(C)C Chemical compound CC1=C(CC2=CC3=C(C=C2C(=O)N2CCC2)C(=O)C(C(=O)O)=CN3C(C)C)C=CC=C1.CC1=C(CC2=CC3=C(C=C2C(=O)N2CCC2)C(=O)C(C(=O)O)=CN3C2CC2)C=CC=C1.CC1=C(CC2=CC3=C(C=C2C(=O)N2CCC2)C(=O)C(C(=O)O)=CN3CC(C)C)C=CC=C1.CC1=CC(C)=NN1CC1=CC2=C(C=C1C(=O)N1CCC1)C(=O)C(C(=O)O)=CN2CC(C)C YNLWJOALGHYDIS-UHFFFAOYSA-N 0.000 description 1
- LWPWUQNFLHSPBN-UHFFFAOYSA-N CC1=C(CC2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3C(C)C)C=CC=C1 Chemical compound CC1=C(CC2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3C(C)C)C=CC=C1 LWPWUQNFLHSPBN-UHFFFAOYSA-N 0.000 description 1
- BGRMVNZWKDKNMR-UHFFFAOYSA-N CC1=C(CC2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)C=CC=C1 Chemical compound CC1=C(CC2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)C=CC=C1 BGRMVNZWKDKNMR-UHFFFAOYSA-N 0.000 description 1
- DKVMOINQCHBDHQ-UHFFFAOYSA-N CC1=CC(C(F)(F)F)=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1 Chemical compound CC1=CC(C(F)(F)F)=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1 DKVMOINQCHBDHQ-UHFFFAOYSA-N 0.000 description 1
- XALOLFNCWUPZIT-UHFFFAOYSA-N CC1=CC(C)=NC1.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CBr.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CN1N=C(C)C=C1C Chemical compound CC1=CC(C)=NC1.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CBr.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CN1N=C(C)C=C1C XALOLFNCWUPZIT-UHFFFAOYSA-N 0.000 description 1
- CZCQMSNWQFOYHV-UHFFFAOYSA-N CC1=CC([N+](=O)[O-])=CC=C1C(=O)O.CO.COC(=O)C1=CC=C([N+](=O)[O-])C=C1C Chemical compound CC1=CC([N+](=O)[O-])=CC=C1C(=O)O.CO.COC(=O)C1=CC=C([N+](=O)[O-])C=C1C CZCQMSNWQFOYHV-UHFFFAOYSA-N 0.000 description 1
- ZPAKXJFXEIDXQE-UHFFFAOYSA-N CC1=CC2=C(C=C1CC1=C(C)NN=C1C)N(C(C)C)C=C(C(=O)O)C2=O Chemical compound CC1=CC2=C(C=C1CC1=C(C)NN=C1C)N(C(C)C)C=C(C(=O)O)C2=O ZPAKXJFXEIDXQE-UHFFFAOYSA-N 0.000 description 1
- NNWJITPLQWHYBY-UHFFFAOYSA-N CC1=CC2=C(C=C1N(C)CC1=CC=CC=C1)N(C(C)C)C=C(C(=O)O)C2=O Chemical compound CC1=CC2=C(C=C1N(C)CC1=CC=CC=C1)N(C(C)C)C=C(C(=O)O)C2=O NNWJITPLQWHYBY-UHFFFAOYSA-N 0.000 description 1
- YWDXITKLQWOMKU-UHFFFAOYSA-N CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1.CCN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2 Chemical compound CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1.CCN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2 YWDXITKLQWOMKU-UHFFFAOYSA-N 0.000 description 1
- DXWPTCOBMRQQAX-UHFFFAOYSA-N CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC2=CC=CC=C2)=C1 Chemical compound CC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC2=CC=CC=C2)=C1 DXWPTCOBMRQQAX-UHFFFAOYSA-N 0.000 description 1
- LARQEFZMDCYRQJ-UHFFFAOYSA-N CC1=CC=CC(CNC2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1 Chemical compound CC1=CC=CC(CNC2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC(C)C)=C1 LARQEFZMDCYRQJ-UHFFFAOYSA-N 0.000 description 1
- RDUXIOSMVIKIAH-UHFFFAOYSA-N CCBr.CCOC(=O)C1=CN(CC)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O Chemical compound CCBr.CCOC(=O)C1=CN(CC)C2=C(C=C(F)C(Cl)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Cl)=C2)C1=O RDUXIOSMVIKIAH-UHFFFAOYSA-N 0.000 description 1
- VKQJVEOQPIBARI-UHFFFAOYSA-N CCN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CCN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CNCC1=CC=CC=C1 Chemical compound CCN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CCN1C=C(C(=O)O)C(=O)C2=C1C=C(N(C)CC1=CC=CC=C1)C(F)=C2.CNCC1=CC=CC=C1 VKQJVEOQPIBARI-UHFFFAOYSA-N 0.000 description 1
- FMXXAJDFZGFHCS-UHFFFAOYSA-N CCN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CCOC(=O)C1=CN(CC)C2=C(C=C(F)C(Cl)=C2)C1=O Chemical compound CCN1C=C(C(=O)O)C(=O)C2=C1C=C(Cl)C(F)=C2.CCOC(=O)C1=CN(CC)C2=C(C=C(F)C(Cl)=C2)C1=O FMXXAJDFZGFHCS-UHFFFAOYSA-N 0.000 description 1
- CGGHSTUMIGBRIE-MNZOIHNJSA-N CCO/C=C(/C(C)=O)C(=O)OCC.CCOC(=O)C(=CNC1=CC=C(C(=O)OC)C(CN2N=C(C)C=C2C)=C1)C(=O)OCC.COC(=O)C1=CC=C(N)C=C1CN1N=C(C)C=C1C Chemical compound CCO/C=C(/C(C)=O)C(=O)OCC.CCOC(=O)C(=CNC1=CC=C(C(=O)OC)C(CN2N=C(C)C=C2C)=C1)C(=O)OCC.COC(=O)C1=CC=C(N)C=C1CN1N=C(C)C=C1C CGGHSTUMIGBRIE-MNZOIHNJSA-N 0.000 description 1
- BPOXDYKGRLAARL-QBUDOIDPSA-N CCO/C=C(/C(C)=O)C(=O)OCC.CCOC(=O)C(=CNC1=CC=C(F)C(Cl)=C1)C(=O)OCC.NC1=CC=C(F)C(Cl)=C1 Chemical compound CCO/C=C(/C(C)=O)C(=O)OCC.CCOC(=O)C(=CNC1=CC=C(F)C(Cl)=C1)C(=O)OCC.NC1=CC=C(F)C(Cl)=C1 BPOXDYKGRLAARL-QBUDOIDPSA-N 0.000 description 1
- CLBIFWNJMRFGCM-XIDBHWPPSA-N CCOC(=O)C(/C=N/C1=CC=C(F)C(Br)=C1)C(=O)OCC.CCOC(=O)C1=CNC2=C(C=C(F)C(Br)=C2)C1=O Chemical compound CCOC(=O)C(/C=N/C1=CC=C(F)C(Br)=C1)C(=O)OCC.CCOC(=O)C1=CNC2=C(C=C(F)C(Br)=C2)C1=O CLBIFWNJMRFGCM-XIDBHWPPSA-N 0.000 description 1
- PKPNCNAWGINABV-JUEUMZLJSA-N CCOC(=O)C(/C=N/C1=CC=C(F)C(Br)=C1)C(=O)OCC.CCOC=C(C(=O)OCC)C(=O)OCC.NC1=CC=C(F)C(Br)=C1 Chemical compound CCOC(=O)C(/C=N/C1=CC=C(F)C(Br)=C1)C(=O)OCC.CCOC=C(C(=O)OCC)C(=O)OCC.NC1=CC=C(F)C(Br)=C1 PKPNCNAWGINABV-JUEUMZLJSA-N 0.000 description 1
- QPRZPOQQVKKOKE-UHFFFAOYSA-N CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Br)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(N(C)CC3=CC=CS3)=C2)C1=O.CNCC1=CC=CS1 Chemical compound CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Br)=C2)C1=O.CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(N(C)CC3=CC=CS3)=C2)C1=O.CNCC1=CC=CS1 QPRZPOQQVKKOKE-UHFFFAOYSA-N 0.000 description 1
- IYGVIMVYEGDITO-UHFFFAOYSA-N CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Br)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Br)=C2)C1=O Chemical compound CCOC(=O)C1=CN(CC(C)C)C2=C(C=C(F)C(Br)=C2)C1=O.CCOC(=O)C1=CNC2=C(C=C(F)C(Br)=C2)C1=O IYGVIMVYEGDITO-UHFFFAOYSA-N 0.000 description 1
- PURJQANMWXXXFJ-UHFFFAOYSA-N CCOC(=O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O.O=C(O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O Chemical compound CCOC(=O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O.O=C(O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O PURJQANMWXXXFJ-UHFFFAOYSA-N 0.000 description 1
- UCYNVLSXHWHZAX-UHFFFAOYSA-N CNCC1=CC(OC)=CC=C1.COC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC2=CC=CC=C2)=C1.O=C(O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O Chemical compound CNCC1=CC(OC)=CC=C1.COC1=CC=CC(CN(C)C2=CC3=C(C=C2F)C(=O)C(C(=O)O)=CN3CC2=CC=CC=C2)=C1.O=C(O)C1=CN(CC2=CC=CC=C2)C2=C(C=C(F)C(Cl)=C2)C1=O UCYNVLSXHWHZAX-UHFFFAOYSA-N 0.000 description 1
- AUSVFBMKPZLKBX-UHFFFAOYSA-N COC(=O)C1=CC=C(N)C=C1CN1N=C(C)C=C1C.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CN1N=C(C)C=C1C Chemical compound COC(=O)C1=CC=C(N)C=C1CN1N=C(C)C=C1C.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CN1N=C(C)C=C1C AUSVFBMKPZLKBX-UHFFFAOYSA-N 0.000 description 1
- OLBYMALPHARRPX-UHFFFAOYSA-N COC(=O)C1=CC=C([N+](=O)[O-])C=C1C.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CBr Chemical compound COC(=O)C1=CC=C([N+](=O)[O-])C=C1C.COC(=O)C1=CC=C([N+](=O)[O-])C=C1CBr OLBYMALPHARRPX-UHFFFAOYSA-N 0.000 description 1
- 206010007279 Carcinoid tumour of the gastrointestinal tract Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010073140 Clear cell sarcoma of soft tissue Diseases 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 208000017259 Extragonadal germ cell tumor Diseases 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108091052347 Glucose transporter family Proteins 0.000 description 1
- 102000042092 Glucose transporter family Human genes 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021042 Hypopharyngeal cancer Diseases 0.000 description 1
- 206010056305 Hypopharyngeal neoplasm Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 201000011062 Li-Fraumeni syndrome Diseases 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 206010025312 Lymphoma AIDS related Diseases 0.000 description 1
- 208000004059 Male Breast Neoplasms Diseases 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 208000030070 Malignant epithelial tumor of ovary Diseases 0.000 description 1
- 206010073059 Malignant neoplasm of unknown primary site Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 229910004749 OS(O)2 Inorganic materials 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 1
- 206010033268 Ovarian low malignant potential tumour Diseases 0.000 description 1
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 208000021161 Plasma cell disease Diseases 0.000 description 1
- 201000008199 Pleuropulmonary blastoma Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000009359 Sezary Syndrome Diseases 0.000 description 1
- 208000021388 Sezary disease Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 206010068771 Soft tissue neoplasm Diseases 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 206010044407 Transitional cell cancer of the renal pelvis and ureter Diseases 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 206010046431 Urethral cancer Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- 230000006682 Warburg effect Effects 0.000 description 1
- 208000000208 Wet Macular Degeneration Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- GZQQOTVESKKPDB-UHFFFAOYSA-N [C-]#[N+]C1=CC2=C(C=C1CC1=C(C)NN=C1C)N(C(C)C)C=C(C(=O)O)C2=O Chemical compound [C-]#[N+]C1=CC2=C(C=C1CC1=C(C)NN=C1C)N(C(C)C)C=C(C(=O)O)C2=O GZQQOTVESKKPDB-UHFFFAOYSA-N 0.000 description 1
- WEZCJAHYWCZTGT-UHFFFAOYSA-N [C-]#[N+]C1=CC2=C(C=C1N(C)CC1=CC=CC=C1)N(C(C)C)C=C(C(=O)O)C2=O Chemical compound [C-]#[N+]C1=CC2=C(C=C1N(C)CC1=CC=CC=C1)N(C(C)C)C=C(C(=O)O)C2=O WEZCJAHYWCZTGT-UHFFFAOYSA-N 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- HGQULGDOROIPJN-UHFFFAOYSA-N azetidin-1-ium;chloride Chemical compound Cl.C1CNC1 HGQULGDOROIPJN-UHFFFAOYSA-N 0.000 description 1
- PVXOUGHWLCBJOW-UHFFFAOYSA-N azetidine-1-carboxamide Chemical compound NC(=O)N1CCC1 PVXOUGHWLCBJOW-UHFFFAOYSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical class [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 201000008873 bone osteosarcoma Diseases 0.000 description 1
- 208000012172 borderline epithelial tumor of ovary Diseases 0.000 description 1
- 239000012152 bradford reagent Substances 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 201000002143 bronchus adenoma Diseases 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 208000011654 childhood malignant neoplasm Diseases 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 201000000292 clear cell sarcoma Diseases 0.000 description 1
- 238000007398 colorimetric assay Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 238000003271 compound fluorescence assay Methods 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 1
- 125000004966 cyanoalkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- KFGVRWGDTLZAAO-UHFFFAOYSA-N cyclopenta-1,3-diene dicyclohexyl(cyclopenta-1,3-dien-1-yl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.C1CCC(CC1)P(C1CCCCC1)c1ccc[cH-]1 KFGVRWGDTLZAAO-UHFFFAOYSA-N 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- CQXYZKIGJFTOFI-UHFFFAOYSA-N diethyl 2-[[3-[(3,5-dimethylpyrazol-1-yl)methyl]-4-methoxycarbonylanilino]methylidene]propanedioate Chemical compound C(C)OC(C(C(=O)OCC)=CNC1=CC(=C(C=C1)C(=O)OC)CN1N=C(C=C1C)C)=O CQXYZKIGJFTOFI-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- OLAMWIPURJGSKE-UHFFFAOYSA-N et2o diethylether Chemical compound CCOCC.CCOCC OLAMWIPURJGSKE-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- VAKBWBGHUCFAIR-UHFFFAOYSA-N ethyl 1-benzyl-7-chloro-6-fluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=CC(Cl)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1CC1=CC=CC=C1 VAKBWBGHUCFAIR-UHFFFAOYSA-N 0.000 description 1
- WQCBYDONXREJEJ-UHFFFAOYSA-N ethyl 6-(azetidine-1-carbonyl)-7-[(3,5-dimethylpyrazol-1-yl)methyl]-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylate Chemical compound N1(CCC1)C(=O)C=1C=C2C(C(=CN(C2=CC=1CN1N=C(C=C1C)C)CC(C)C)C(=O)OCC)=O WQCBYDONXREJEJ-UHFFFAOYSA-N 0.000 description 1
- SDBXTVIRSNLZHA-UHFFFAOYSA-N ethyl 6-fluoro-1-(2-methylpropyl)-7-[methyl(thiophen-2-ylmethyl)amino]-4-oxoquinoline-3-carboxylate Chemical compound CN(CC=1SC=CC=1)C1=C(C=C2C(C(=CN(C2=C1)CC(C)C)C(=O)OCC)=O)F SDBXTVIRSNLZHA-UHFFFAOYSA-N 0.000 description 1
- ZQCMKIVWGWWYCQ-UHFFFAOYSA-N ethyl 7-bromo-6-fluoro-1-(2-methylpropyl)-4-oxoquinoline-3-carboxylate Chemical compound BrC1=C(C=C2C(C(=CN(C2=C1)CC(C)C)C(=O)OCC)=O)F ZQCMKIVWGWWYCQ-UHFFFAOYSA-N 0.000 description 1
- XAVKVCAQGDGQCE-UHFFFAOYSA-N ethyl 7-bromo-6-fluoro-4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=C(Br)C(F)=CC2=C(O)C(C(=O)OCC)=CN=C21 XAVKVCAQGDGQCE-UHFFFAOYSA-N 0.000 description 1
- NGBZZCXZVDYZQK-UHFFFAOYSA-N ethyl 7-chloro-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylate Chemical compound ClC1=C(F)C=C2C(=O)C(C(=O)OCC)=CN(CC)C2=C1 NGBZZCXZVDYZQK-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 201000008819 extrahepatic bile duct carcinoma Diseases 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 201000007116 gestational trophoblastic neoplasm Diseases 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000000899 immune system response Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 201000006721 lip cancer Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 208000018769 loss of vision Diseases 0.000 description 1
- 231100000864 loss of vision Toxicity 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 201000003175 male breast cancer Diseases 0.000 description 1
- 208000010907 male breast carcinoma Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 210000000716 merkel cell Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 208000037970 metastatic squamous neck cancer Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- PGNKFDOPHHNVNF-UHFFFAOYSA-N methyl 2-(bromomethyl)-4-nitrobenzoate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C=C1CBr PGNKFDOPHHNVNF-UHFFFAOYSA-N 0.000 description 1
- JJHCLPDHYBSSHC-UHFFFAOYSA-N methyl 2-methyl-4-nitrobenzoate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C=C1C JJHCLPDHYBSSHC-UHFFFAOYSA-N 0.000 description 1
- YQQOFPMCJLZVHX-UHFFFAOYSA-N methyl 4-amino-2-[(3,5-dimethylpyrazol-1-yl)methyl]benzoate Chemical compound NC1=CC(=C(C(=O)OC)C=C1)CN1N=C(C=C1C)C YQQOFPMCJLZVHX-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 206010051747 multiple endocrine neoplasia Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000002071 myeloproliferative effect Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- WGDFDUYIZTVXJR-UHFFFAOYSA-N n-methyl-1-(1-methylpiperidin-4-yl)methanamine Chemical compound CNCC1CCN(C)CC1 WGDFDUYIZTVXJR-UHFFFAOYSA-N 0.000 description 1
- WMBCUXKYKVTJRF-UHFFFAOYSA-N n-methyl-1-(oxan-4-yl)methanamine Chemical compound CNCC1CCOCC1 WMBCUXKYKVTJRF-UHFFFAOYSA-N 0.000 description 1
- JFLPPELZYKHKQZ-UHFFFAOYSA-N n-methyl-1-[3-(trifluoromethyl)phenyl]methanamine Chemical compound CNCC1=CC=CC(C(F)(F)F)=C1 JFLPPELZYKHKQZ-UHFFFAOYSA-N 0.000 description 1
- MCSAQVGDZLPTBS-UHFFFAOYSA-N n-methyl-1-pyridin-3-ylmethanamine Chemical compound CNCC1=CC=CN=C1 MCSAQVGDZLPTBS-UHFFFAOYSA-N 0.000 description 1
- TTXJMSRLGMWEJZ-UHFFFAOYSA-N n-methyl-1-thiophen-2-ylmethanamine Chemical compound CNCC1=CC=CS1 TTXJMSRLGMWEJZ-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 208000022982 optic pathway glioma Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 201000005443 oral cavity cancer Diseases 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 208000021284 ovarian germ cell tumor Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 201000002530 pancreatic endocrine carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 201000003113 pineoblastoma Diseases 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 208000010916 pituitary tumor Diseases 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 208000030859 renal pelvis/ureter urothelial carcinoma Diseases 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000000956 solid--liquid extraction Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 208000037969 squamous neck cancer Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000031068 symbiosis, encompassing mutualism through parasitism Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 208000008732 thymoma Diseases 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 208000029387 trophoblastic neoplasm Diseases 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000002568 urticarial effect Effects 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to compounds useful as monocarboxylate transport modulators.
- the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
- tumors display altered cellular metabolism, in which cancer cells exhibit high rate of glucose consumption. Tumors contain well oxygenated (aerobic), and poorly oxygenated (hypoxic) regions. Compared to normal cells, cancer cells are heavily dependent upon either aerobic glycolysis (Warburg effect, 1956) or anerobic glycolysis (in hypoxic regions) for energy (ATP) production. This glycolytic switch by highly proliferating and hypoxic cancer cells provides the energy and biosynthetic needs for cancer cell survival. To maintain this metabolic phenotype, cancer cells up regulate a series of proteins, including glycolytic enzymes and pH regulators; monocarboxylate transporters (MCTs) that will facilitate the efflux of lactate co-transported with a proton. This fundamental difference between normal cells and cancer cells has been applied for cancer diagnosis, but has not been applied for cancer therapy.
- MCTs monocarboxylate transporters
- MCTs mediate influx and efflux of monocarboxylates such as lactate, pyruvate, ketone bodies (acetoacetate and beta-hydroxybutyrate) across cell membranes. These monocarboxylates play essential roles in carbohydrate, amino acid, and fat metabolism in mammalion cells, and must be rapidly transported across plasma membrane of cells. MCTs catalyse the transport of these solutes via a facilitative diffusion mechanism that requires co-transport of protons. Monocarboxylates such as lactate, pyruvate, and ketone bodies play a central role in cellular metabolism and metabolic communications among tissues. Lactate is the end product of aerobic glycolysis. Lactate has recently emerged as a critical regulator of cancer development, invasion, and metastasis. Tumor lactate levels correlate well with metastasis, tumor recurrence, and poor prognosis (MCT Lactate Meta_JClinInvest_2013).
- MCTs are 12-span transmembrane proteins with N- and C-terminus in cytosolic domain, and are members of solute carrier SLC16A gene family. MCT family contains 14 members, and so far MCT1, MCT2, MCT3, and MCT4 are well characterized [Biochemical Journal (1999), 343:281-299].
- MCT1 and MCT4 are dependent upon interaction of other protein such as the chaperone CD147 (basigin, EMMPRIN), a member of immunoglobulin super family with a single transmembrane helix. Many studies have shown the tight association of CD147 and MCT1 and MCT4 [Future Oncology (2010), (1), 127]. CD147 acts as a chaperone to bring MCT1 and MCT4 to the plasma membrane and remain closely associated for the essential function of MCTs.
- CD147 basic, EMMPRIN
- Malignant tumors contain aerobic and hypoxic regions, and the hypoxia increases the risk of cancer invasion and metastasis. Tumor hypoxia leads to treatment failure, relapse, and patient mortality as these hypoxic cells are generally resistant to standard chemo- and radiation therapy.
- cancer cells metabolize glucose into lactate whereas nearby aerobic cancer cells take up this lactate via the MCT1 for oxidative phosphorylation (OXPHOS).
- OXPHOS oxidative phosphorylation
- cancer cells up regulate glucose transporters and consume large quantities of glucose.
- Cancer cells also up regulate glycolytic enzymes and convert glucose into lactate, which is then efflux out of cell via MCT4.
- the nearby aerobic cancer cells take up this lactate via MCT1 for energy generation through OXPHOS.
- the limited glucose availability to the tumor is used most efficiently via synergistic metabolic symbiosis. This utilization of lactate as an energy substitute for survival prevents the aerobic cells from consuming large quantities of glucose.
- the invention relates to compounds that are effective as monocarboxylate transport modulators.
- Such compounds have of formula I:
- the invention in another aspect relates to methods for inhibiting monocarboxylate transport.
- the methods comprise contacting a monocarboxylate transporter with an effective amount of a compound described herein.
- the invention in another aspect, relates to a method for treating a disorder associated with monocarboxylate transport comprising administering a compound described herein.
- disorders include cancer and other neoplastic disorders, inflammatory diseases, disorders of abnormal tissue growth, metabolic disorders, diabetes, obesity, malaria, and tissue and organ rejection.
- the present invention relates to a compound of formula I:
- C 1-6 alkyl 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers or enantiomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.
- reference to a certain element such as hydrogen or H is meant (if appropriate) to include all isotopes of that element, for example, deuterium and tritium for hydrogen.
- alkyl as used herein means a straight- or branched-chain hydrocarbon having from one to eight carbon atoms, and includes, for example, and without being limited thereto, methyl, ethyl, propyl, isopropyl, t-butyl and the like. Substituted alkyl includes, for example, and without being limited thereto, haloalkyl, hydroxyalkyl, cyanoalkyl, and the like. This is applied to any of the groups mentioned herein, such as substituted “alkenyl”, “alkynyl”, “aryl”, etc.
- alkenyl as used herein means a straight- or branched-chain aliphatic hydrocarbon having at least one double bond.
- the alkene may have from two to eight carbon atoms, and includes, for example, and without being limited thereto, ethenyl, 1-propenyl, 1-butenyl and the like.
- alkenyl encompass radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
- alkynyl as used herein means a straight- or branched-chain aliphatic hydrocarbon having at least one triple bond.
- the alkyne may have from two to eight carbon atoms, and includes, for example, and without being limited thereto, 1-propynyl (propargyl), 1-butynyl and the like.
- cycloalkyl as used herein means an aliphatic carbocyclic system (which may be unsaturated) containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused.
- the ring(s) may have from three to seven carbon atoms, and includes, for example, and without being limited thereto, cyclopropyl, cyclohexyl, cyclohexenyl and the like.
- heterocycloalkyl as used herein means a heterocyclic system (which may be unsaturated) having at least one heteroatom selected from N, S and/or O and containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused.
- the ring(s) may have a three- to seven-membered cyclic group and includes, for example, and without being limited thereto, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.
- heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.
- unsaturated means that a moiety has one or more units of unsaturation.
- alkoxy as used herein means a straight- or branched-chain oxygen-containing hydrocarbon; in one aspect, having from one to eight carbon atoms and includes, for example, and without being limited thereto, methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
- halo or “halogen” includes, for example, and without being limited thereto, fluoro, chloro, bromo, and iodo, in both radioactive and non-radioactive forms.
- alkylene as used herein means a difunctional branched or unbranched saturated hydrocarbon; in one aspect, having one to eight carbon atoms, and includes, for example, and without being limited thereto, methylene, ethylene, n-propylene, n-butylene and the like.
- aryl alone or in combination, as used herein means a carbocyclic aromatic system containing one or more rings. In particular embodiments, aryl is one, two or three rings. In one aspect, the aryl has five to twelve ring atoms.
- aryl encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
- the “aryl” group may have 1 to 4 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
- heteroaryl alone or in combination, as used herein means an aromatic system having at least one heteroatom selected from N, S and/or O and containing one or more rings.
- heteroaryl is one, two or three rings.
- the heteroaryl has five to twelve ring atoms.
- heteroaryl encompasses heteroaromatic groups such as triazolyl, imidazolyl, pyrrolyl, tetrazolyl, pyridyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl, thiazolyl and the like.
- the “heteroaryl” group may have 1 to 4 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
- substituents and substitution patterns on the compounds of the invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure results.
- compounds of the invention may contain “optionally substituted” moieties.
- substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
- an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
- Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
- stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
- Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH 2 ) 0-4 R o ; —(CH 2 ) 0-40 R o ; —O(CH 2 ) 0-4 R o , —O—(CH 2 ) 0-4 C(O)OR o ;)—(CH 2 ) 0-4 CH(OR o ) 2 , —(CH 2 ) 0-4 SR o ; —(CH 2 ) 0-4 Ph, which may be substituted with R o ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph which may be substituted with R o ; —CH ⁇ CHPh, which may be substituted with R o ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl which may be substituted with R o ; —NO 2 ; —CN;
- Suitable monovalent substituents on R o are independently halogen, —(CH 2 ) 0-2 R ⁇ , -(haloR ⁇ ), —(CH 2 ) 0-2 OH, —(CH 2 ) 0-2 OR ⁇ , —(CH 2 ) 0-2 CH(OR 108 ) 2 ; —O(haloR ⁇ ), —CN, —N 3 , —(CH 2 ) 0-2 C(O)R ⁇ , —(CH 2 ) 0-2 C(O)OH, —(CH 2 ) 0-2 C(O)OR ⁇ , —(CH 2 ) 0-2 SR ⁇ , —(CH 2 ) 0-2 SH, —(CH 2 ) 0-2 NH 2 , —(CH 2 ) 0-2 NHR ⁇ , —(CH 2
- Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ⁇ O, ⁇ S, ⁇ NNR* 2 , ⁇ NNHC(O)R*, ⁇ NNHC(O)OR*, ⁇ NNHS(O) 2 R*, ⁇ NR*, ⁇ NOR*, —O(C(R* 2 )) 2-3 O—, or —S(C(R* 2 )) 2-3 S—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR* 2 ) 2-3 O—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Suitable substituents on the aliphatic group of R* include halogen, —R ⁇ , -(haloR ⁇ ), —OH, —OR ⁇ , —O(haloR ⁇ ), —CN, —C(O)OH, —C(O)OR ⁇ , —NH 2 , —NHR ⁇ , —NR ⁇ 2 , or —NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R ⁇ , —NR ⁇ 2 , —C(O)R ⁇ , —C(O)OR ⁇ , —C(O)C(O)R ⁇ , —C(O)CH 2 C(O)R ⁇ , —S(O) 2 R ⁇ , —S(O) 2 NR ⁇ , —C(S)NR ⁇ 2 , —C(NH)NR ⁇ 2 , or —N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences
- Suitable substituents on the aliphatic group of R ⁇ are independently halogen, —R ⁇ , —(haloR ⁇ ), —OH, —OR ⁇ , —O(haloR ⁇ ), —CN, —C(O)OH, —C(O)OR ⁇ , —NH 2 , —NHR ⁇ , —NR ⁇ 2 , or —NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 )o_iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art.
- Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
- Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
- organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
- structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
- structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
- compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
- Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
- exemplary inorganic acids which form suitable salts include, but are not limited thereto, hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
- exemplary organic acids which form suitable salts include the mono-, di- and tricarboxylic acids.
- Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.
- Either the mono- or di-acid salts can be formed and such salts can exist in either a hydrated, solvated or substantially anhydrous form.
- the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
- Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
- a “pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formula I or any of its intermediates.
- Illustrative inorganic bases which form suitable salts include, but are not limited thereto, lithium, sodium, potassium, calcium, magnesium or barium hydroxides.
- Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia. The selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
- Acid addition salts of the compounds of Formula I are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid.
- Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
- base addition salts such as sodium, potassium and ammonium salts
- solvates and hydrates of compounds of the invention are also included within the scope of the invention. The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, well known to one skilled in the art.
- stereoisomers is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
- treat or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to inhibit or slow the appearance of symptoms of the named disorder or condition.
- therapeutically effective amount means an amount of the compound which is effective in treating or lessening the severity of one or more symptoms of a disorder or condition.
- pharmaceutically acceptable carrier means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient.
- a pharmaceutical composition i.e., a dosage form capable of administration to the patient.
- pharmaceutically acceptable oil typically used for parenteral administration.
- the present invention relates to a compound of formula II,
- C 1-6 alkyl 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- the compound has the following structure III:
- C 1-6 alkyl 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Z is oxygen.
- A is carbon.
- n is equal to 0.
- R 3 is hydrogen
- Y is oxygen
- R 2 is hydrogen.
- the base addition salt is formed from sodium, potassium, magnesium, calcium.
- the compound has the following structure:
- R 1 , R 4 , X, and Ar is as defined above and described herein.
- R 1 is a —C(O)R o .
- X is a methylene or substituted methylene.
- the compound has the following structure:
- R′′ is an amine (e.g., azetidine).
- Ar is substituted phenyl (e.g. trifluoromethyl phenyl) and the other is substituted pyrazole (e.g. dimethyl pyrazole).
- R 4 is substituted or unsubstituted alkyl (e.g., isopropyl, isobutyl, cyclopropyl).
- the compound is selected from;
- the compound has the following structure:
- R 1 , R 4 , X, n, W, and Ar is as defined above and described herein.
- X is nitrogen.
- n is equal to 1.
- W is a bond, and a base addition salt is formed from sodium, potassium, magnesium, or calcium.
- the compound has the following structure:
- R′′ is an alkyl (e.g., methyl).
- R 1 is a halogen (e.g., fluoro).
- R 1 is an amide (e.g., azetidino amide).
- Ar is unsubstituted or substituted phenyl (e.g. p-chlorophenyl).
- R 4 is substituted or unsubstituted alkyl (e.g., isopropyl, isobutyl, ethyl, benzyl).
- the compound is selected from:
- the compound has the following structure:
- the compound is selected from;
- the compound has the following structure:
- the compound has the following structure:
- the compound is selected from:
- the invention relates to a method of treating a neoplastic or inflammatory or metabolic disorder in a subject, comprising administering a pharmaceutically effective amount of a compound or composition described herein.
- Also provided herein are methods of treating a disease associated with expression or activity of MCT1, MCT2, MCT3, MCT4, CD147, NFkB, p53 in a subject comprising administering to the patient a therapeutically effective amount of a compound described herein.
- hematologic malignancies leukemias, lymphomas, myelomas, myelodysplastic and myeloproliferative syndromes
- solid tumors solid tumors
- inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriatic arthritis, multiple scelorisis, systemic lupus, systemic sclerosis, vasculitis syndromes (small, medium and large vessel),atherosclerosis, psoriasis and other dermatological inflammatory disorders (such as pemphigous, pemphigoid, allergic dermatitis),and urticarial syndromes comprising administering a compound represented by formula I.
- the compounds and compositions described herein may be administered intravenously, intraperitoneally, or orally.
- the present invention provides a compound selected from:
- the invention relates to a composition
- a composition comprising a compound described herein, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- the amount of compound in compositions will normally be an amount effective to measurably inhibit monocarboxylate transport, in a biological sample or in a patient.
- compositions containing a fraction of the effective amount may be employed for multiple dosing.
- a composition of this invention is formulated for oral administration, intravenous, subcutaneous, intraperitoneal or dramatological application to a patient.
- patient means an animal.
- the animal is a mammal.
- the patient is a veterinary patient (i.e., a non-human mammal patient).
- the patient is a dog.
- the patient is a human.
- Compounds and compositions described herein are generally useful for the inhibition of monocarboxylate transport.
- the activity of a compound may be assayed in vitro, in vivo or in a cell line.
- Detailed conditions for assaying a compound utilized as an inhibitor of monocarboxylate transport are set forth in the Examples below.
- the compounds and compositions described herein can be administered to cells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., in vivo, to treat and/or diagnose a variety of disorders, including those described herein below.
- the term “treat” or “treatment” is defined as the application or administration of a compound, alone or in combination with, a second compound to a subject, e.g., a patient, or application or administration of the compound to an isolated tissue or cell, e.g., cell line, from a subject, e.g., a patient, who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder, one or more symptoms of the disorder or the predisposition toward the disorder (e.g., to reduce at least one symptom of the disorder or to delay onset of at least one symptom of the disorder).
- a disorder e.g., a disorder as described herein
- a symptom of a disorder e.g., a disorder as described herein
- a predisposition toward a disorder e.
- an amount of a compound effective to treat a disorder refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.
- a prophylactically effective amount of the compound refers to an amount effective, upon single- or multiple-dose administration to the subject, in reducing or delaying the occurrence of the onset or recurrence of a disorder or a symptom of the disorder.
- the term “subject” is intended to include human and non-human animals.
- exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein or a normal subject.
- non-human animals of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, cow, pig, etc, and companion animals (dog, cat, horse etc).
- the present invention provides a method for treating a monocarboxylate transport-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.
- monocarboxylate transport-mediated disorder or condition means any disease or other deleterious condition in which monocarboxylate transport is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which monocarboxylate transport is known to play a role. Specifically, the present invention relates to a method of treating or lessening the severity of a proliferative disorder. Disorders are set forth in detail below.
- a compound or composition described herein can be used to treat a neoplastic disorder.
- a “neoplastic disorder” is a disease or disorder characterized by cells that have the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth.
- neoplastic disorders include: carcinoma, sarcoma, metastatic disorders (e.g., tumors arising from prostate, colon, lung, breast, cervical, ovarian, liver, melanoma, brain, —CNS, head and neck, osteosarcoma, gastrointestinal, pancreatic, hematopoietic neoplastic disorders, e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders, and metastatic tumors.
- Prevalent cancers include: breast, prostate, colon, lung, liver, and pancreatic cancers. Treatment with the compound may be in an amount effective to ameliorate at least one symptom of the neoplastic disorder, e.g., reduced cell proliferation, reduced tumor mass, etc.
- the disclosed methods are useful in the treatment of cancer, including for example, solid tumors, soft tissue tumors, and metastases thereof, as well as in familial cancer syndromes such as Li Fraumeni Syndrome, Familial Breast-Ovarian Cancer (BRCA1 or BRAC2 mutations) Syndromes, and others.
- the disclosed methods are also useful in treating non-solid cancers.
- Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the various organ systems, such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary (e.g., renal, urothelial, or testicular tumors) tracts, pharynx, prostate, and ovary.
- malignancies e.g., sarcomas, adenocarcinomas, and carcinomas
- gastrointestinal e.g., colon
- genitourinary e.g., renal, urothelial, or testicular tumors
- Exemplary adenocarcinomas include colorectal cancers, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, and cancer of the small intestine.
- Exemplary cancers described by the National Cancer Institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymom
- a compound described herein is administered together with an additional cancer treatment.
- exemplary cancer treatments include, for example: chemotherapy, targeted therapies such as antibody therapies, kinase inhibitors, immunotherapy, cancer metabolism therapies, hormonal therapy, and anti-angiogenic therapies.
- Angiogenesis is the physiological processes involving the growth of new vessels from pre-existing blood vessels. Angiogenesis is the normal and vital process in growth and development, as well as in wound healing and in granular tissue. However, it is also a fundamental step in the transition of tumors from a dormant state to a malignant one. Angiogenesis may be a target for combating diseases characterized by either poor vascularization or abnormal vasculature. Application of specific compounds that may inhibit the creation of new blood vessels in the body may help combat such diseases.
- blood vessels where there should be none may affect the normal properties of a tissue, increasing the likelihood of failure.
- the absence of blood vessels in a repairing or otherwise metabolically active tissue may inhibit repair or other essential functions.
- ischemic chronic wounds are the results of failure or insufficient blood vessel formation and may be treated by a local expansion of blood vessels, thus bringing new nutrients to the site, facilitating repair.
- Other diseases such as age-related macular degeneration may be created by a local expansion of blood vessels, interfering with normal physiological processes.
- VEGF Vascular endothelial growth factor
- Tumors induce blood vessel growth by secreting various growth factors (e.g. VEGF).
- Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which may supply required nutrients allowing for tumor expansion.
- Angiogenesis therefore represents an attractive target for the treatment of cancer and cardiovascular diseases. It is a potent physiological process that underlies the natural manner in which our bodies responds to a diminution of blood supply to vital organs, namely the production of new collateral vessels to overcome the ischemic insult.
- Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In wet macular degeneration, VEGF causes proliferation of capillaries into the retina.
- Antiangiogenic therapy can include kinase inhibitors targeting vascular endothelial growth factor (VEGF) such as sutinib, sorafenib, or monoclonal antibodies or recerptor “decoys” to VEGF or VEGF-Trap or thalidomide or its analogs (lenalidimide, pomalidomide), or agents targeting non-VEGF angiogenic targets such as fibroblast growth factor (FGF), angiopoietins, or angiostatin, or ensostatin.
- VEGF vascular endothelial growth factor
- FGF fibroblast growth factor
- angiopoietins angiostatin
- angiostatin angiostatin
- the body immune system detects foreign objects and organisms such as bacteria, virus, and other pathogens, and protects the body by eliminating those harmful matters.
- those immune system responses against foreign pathogens or tissues become more harmful to the host, for example, allergies to food and extrinsic antigens such as pollen and respiratory diseases such as asthma.
- strong responses against transplant tissues or organs occur, leading to the rejection of them.
- immunosuppressive drugs are needed to avoid those complications.
- the body's immune system does not exert responses against self-tissues or self-antigens under normal circumstances.
- body exerts a strong immune response against self-tissues aggressively leading to a variety of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, type I diabetes, etc.
- Most immune responses are initiated and controlled by T helper lymphocytes, which respond to antigens.
- rapamycin which disrupts the cytokine such as IL-2-driven T-cell proliferation by interefering with TOR (Target of Rapamycin) function.
- TOR Target of Rapamycin
- rapamycin has been shown to cause significant side effects including hyperlipidemia (Hong et al, Semin. Nephrol., 10(2); 108-125, 2000).
- MCTs may act as biomarkers and compounds and compositions described herein may also be used to treat selectively sub-population of patients who express either MCT1 or MCT4 or both. It is known that a patient's response to a drug may be dependent upon patient's genetic profile and/or the type of the disease. It has been demonstrated that MCT4 is a biomarker that predicts poor overall survival of aggressive triple negative breast cancer patients.
- a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation.
- Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order will be readily understood to the one skilled in the art of organic synthesis. Examples of transformations are given below, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified.
- room temperature and “ambient temperature” shall mean, unless otherwise specified, a temperature between 16 and 25° C.
- Certain quinolone carboxylic acid compounds of Formula I, wherein the R 4 group is an alkyl, B is an aryl or heteroaryl group, and R l group is hydrogen, fluorine, or optionally substituted carboxylic acid, carboxylic ester, carboxy amides, cyano, etc., can be prepared in accordance with general Scheme 1.
- the group Ar is selected from aryl and heteroaryl optionally substituted with one or more substituents and, the X is an alkyl group, and the R 4 group is an alkyl, and R 1 group is hydrogen, fluorine, or optionally substituted amine, carboxylic acid, carboxylic ester, carboxy amides, cyano, etc., can be prepared in accordance with general Scheme 2.
- 3-Chloro-4-fluoroaniline (20 g, 137.4 mmol) was added with toluene (100 mL).
- diethyl-2-(ethoxymethylene) malonate 29.7 g, 137.4 mmol was added at 25° C.
- the reaction mixture was heated at reflux under stirring for 1 h, then cooled to 30° C. and added water (150 mL).
- the mixture was extracted with EtOAc (30 mL ⁇ 3).
- intermediate (3) (3.3 g, 10.13 mmol) was added with THF :Water (1:1) (10 mL).
- 2M KOH solution (20 mL) was added dropwise maintaining the temperature at 0° C.
- the resulting mixture was stirred at room temperature for 2 h and reaction completion was monitored by TLC.
- the mixture was cooled to 0° C. and acidified to pH 3-4 with 4N HCl.
- the solid compound obtain was filtered to obtain 2.1 g of the crude product.
- Example 2 Mother liquor remained from the synthesis of Example 1 was concentrated under reduced pressure to obtain the crude 5b.
- the product was purified by column chromatography (silica gel) to obtain 10 mg of pure 6-(benzyl(methyl)amino)-7-chloro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (5b): Yield, 5%; 1 H NMR (400 MHz, DMSO-d6): ⁇ 15.16 (d, 1H), 8.95 (s,1H), 7.28-8.27 (m, 7H), 4.41-4.43 (d, 2H), 4.3 (s, 2H), 2.74 (s, 3H), 2.1-2.2 (m, 1H), 0.88-0.90 (d, 6H); MS (ESI): 399(M+H); HPLC: 93.57%.
- the intermediate (1) (20 g, 88.01 mmol) was charged with CCl 4 (100 mL). N-bromosuccinimide (39.16g, 220.03 mmol) and AIBN (2.16 g, 13.20 mmol) were added and the resulting mixture was refluxed for 20 h. The reaction mixture was quenched with water (500 mL), extracted with dichloromethane (200 mL ⁇ 3), and the combined organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate.
- the intermediate (4) (5 g, 19.28 mmol) was charged with toluene (100 mL) and diethyl-2-(ethoxymethylene) malonate (4.16 g, 19.28 mmol) was added at 25° C. The reaction mixture was refluxed for 1 h. The reaction mixture was then cooled to room temperature and hexane was added to precipitate the compound.
- the intermediate (7) (0.3 g, 0.682 mmol) was charged with THF/Water(1:1) (5 mL) at 0° C. and LiOH (0.028 g, 0.681 mmol) was added to the the mixture. The resulting mixture was stirred at 0° C. for 30-50 min. The reaction was closely monitored for selective mono hydrolysis by mass spectroscopy and TLC. After completion, the mixture was acidified to pH 2 by 4 N HCl and the product was extracted with dichloromethane (50 mL ⁇ 3). The combined organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate to obtain the crude product.
- the intermediate (8) (0.2 g, 0.47 mmol) was charged with DMF (2 mL). To this reaction mixture, were added azetidine HCl (0.043 g, 0.47 mmol), EDC.HCl (0.094 g, 0.611 mmol) and DMAP (5 mg, 0.047 mmol) and the resulting mixture was stirred for 2 h at room temperature. After completion, the reaction was quenched with water and extracted with EtOAc (50 mL ⁇ 3). The combined organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulphate.
- the intermediate (4) (0.2 g, 0.70 mmol) and N-methyl-1-(pyridin-3-yl)methanamine (0.43 g, 3.42 mmol) were added, and the reaction mixture was heated at 120° C. for 24 h and worked up.
- the reaction mixture was partitioned in dichloromethane/water and the organic layer was separated.
- the organic layer was washed with 30% HCl solution, dried over anhydrous Na 2 SO 4 , and the solvent was removed in vacuo to obtain the crude product.
- the crude product was treated with EtOAc: hexane (50:50) (10 Vol) and heated at 60° C. for 15 min. Then the reaction was brought to room temperature, and the solid was filtered.
- Cytotoxicity of the inhibition of monocarboxylate transporters of the invention was determined and are shown in Table 1.
- the anti-proliferation effect of MCT inhibition was investigated across a panel of solid and haemotological tumor cell lines.
- Cells were routinely cultured in their appropriate growth medium. On day 1, between 5,000 -10,000 cells/well were plated into 96-well plates. 100 ⁇ L of phosphate buffered saline solution was added to the external wells to prevent media evaporation. Plates were incubated overnight at 37° C. in the presence of 5% CO 2. On day 2, dry weight compound stocks were dissolved to a concentration of 20 mM in 100% DMSO.
- lactate medium the medium was replaced by 100 ⁇ L of growth medium and 20 ⁇ L of CellTiter 96 AQ MTS reagent or replaced the media in cells with 100 uL of growth media containing 10% MTT solution,.
- MTS or MTT is bioreduced by NADPH or NADH produced by dehydrogenase enzymes in metabolically active cells into a coloured formazan product that is soluble in tissue culture medium.
- the amount of coloured formazan product is directly proportional to the number of living cells in culture.
- MTT after 4 hr incubation, the media was removed from the plates and the plate was air-dried.
- the inhibition of monocarboxylate transporters of the invention was determined and data are shown in Table II.
- Cells are maintained in their appropriate growth medium (DMEM medium with 4.5 g/L glucose, 4 mM L-glutamine supplemented with 10% FBS and P/S (growth medium).
- DMEM medium with 4.5 g/L glucose, 4 mM L-glutamine supplemented with 10% FBS and P/S (growth medium).
- Cells (500,000 cells/well) were seeded in 24-well plate in growth medium for 6 hours.
- Replace the growth medium with 1 mL lactate medium (10 mM lactate in base DMEM without sodium pyruvate) for overnight.
- Cells were treated with compounds in 1 mL lactate medium for 24 hours.
- the culture medium was collected and centrifuged at 12,000 rpm for 5 minutes at 4° C. to get rid of any cell debris.
- the sample lactic acid concentration can be accurately calculated based on the lactic acid standards.
- the signal was read on a Synergy H4 plate reader using 570 nM measurement wavelength, and the lactate consumption was calculated by medium lactate concentration at start point (10 mM) subtracted the end point.
- the inhibition of monocarboxylate transporters of the invention was determined using 14 CLactate, and the data are shown in Table II.
- Cells are maintained in their appropriate growth medium (DMEM medium with 4.5 g/L glucose, 4 mM L-glutamine supplemented with 10% FBS and P/S (growth medium).
- DMEM medium with 4.5 g/L glucose, 4 mM L-glutamine supplemented with 10% FBS and P/S (growth medium).
- Cell culture surface of 24-well cell culture plates (BD Bioscience) were aseptically coated with 80 ⁇ L poly-lysine (1 mg/mL, Sigma) for 5 mins, then rinsed with sterile cell culture grade water, air-dried for at least 2 hours before introducing cells and medium.
- SiHa cells were seeded in poly-lysine coated 24-well plate at 500,000 cells/well in growth medium for 6 hours.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Tropical Medicine & Parasitology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Transplantation (AREA)
- Child & Adolescent Psychology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
- This application claims priority from U.S. provisional application 62/080,703, filed Nov. 17, 2014, the entire contents of which are incorporated herein by reference.
- The present invention relates to compounds useful as monocarboxylate transport modulators. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
- It has been well demonstrated that tumors display altered cellular metabolism, in which cancer cells exhibit high rate of glucose consumption. Tumors contain well oxygenated (aerobic), and poorly oxygenated (hypoxic) regions. Compared to normal cells, cancer cells are heavily dependent upon either aerobic glycolysis (Warburg effect, 1956) or anerobic glycolysis (in hypoxic regions) for energy (ATP) production. This glycolytic switch by highly proliferating and hypoxic cancer cells provides the energy and biosynthetic needs for cancer cell survival. To maintain this metabolic phenotype, cancer cells up regulate a series of proteins, including glycolytic enzymes and pH regulators; monocarboxylate transporters (MCTs) that will facilitate the efflux of lactate co-transported with a proton. This fundamental difference between normal cells and cancer cells has been applied for cancer diagnosis, but has not been applied for cancer therapy.
- MCTs mediate influx and efflux of monocarboxylates such as lactate, pyruvate, ketone bodies (acetoacetate and beta-hydroxybutyrate) across cell membranes. These monocarboxylates play essential roles in carbohydrate, amino acid, and fat metabolism in mammalion cells, and must be rapidly transported across plasma membrane of cells. MCTs catalyse the transport of these solutes via a facilitative diffusion mechanism that requires co-transport of protons. Monocarboxylates such as lactate, pyruvate, and ketone bodies play a central role in cellular metabolism and metabolic communications among tissues. Lactate is the end product of aerobic glycolysis. Lactate has recently emerged as a critical regulator of cancer development, invasion, and metastasis. Tumor lactate levels correlate well with metastasis, tumor recurrence, and poor prognosis (MCT Lactate Meta_JClinInvest_2013).
- MCTs are 12-span transmembrane proteins with N- and C-terminus in cytosolic domain, and are members of solute carrier SLC16A gene family. MCT family contains 14 members, and so far MCT1, MCT2, MCT3, and MCT4 are well characterized [Biochemical Journal (1999), 343:281-299].
- Regulation and function of MCT1 and MCT4 are dependent upon interaction of other protein such as the chaperone CD147 (basigin, EMMPRIN), a member of immunoglobulin super family with a single transmembrane helix. Many studies have shown the tight association of CD147 and MCT1 and MCT4 [Future Oncology (2010), (1), 127]. CD147 acts as a chaperone to bring MCT1 and MCT4 to the plasma membrane and remain closely associated for the essential function of MCTs.
- Malignant tumors contain aerobic and hypoxic regions, and the hypoxia increases the risk of cancer invasion and metastasis. Tumor hypoxia leads to treatment failure, relapse, and patient mortality as these hypoxic cells are generally resistant to standard chemo- and radiation therapy. In regions of hypoxia, cancer cells metabolize glucose into lactate whereas nearby aerobic cancer cells take up this lactate via the MCT1 for oxidative phosphorylation (OXPHOS). Under hypoxic conditions, cancer cells up regulate glucose transporters and consume large quantities of glucose. Cancer cells also up regulate glycolytic enzymes and convert glucose into lactate, which is then efflux out of cell via MCT4. The nearby aerobic cancer cells take up this lactate via MCT1 for energy generation through OXPHOS. Thus, the limited glucose availability to the tumor is used most efficiently via synergistic metabolic symbiosis. This utilization of lactate as an energy substitute for survival prevents the aerobic cells from consuming large quantities of glucose.
- In one aspect, the invention relates to compounds that are effective as monocarboxylate transport modulators. Such compounds have of formula I:
-
- or a pharmaceutically acceptable salt thereof, wherein:
- n is , 0, 1, or 2;
- W is a bond, C═O, or SO2;
- Z is selected from O, S, N—CN, and NR−;
- R1 is selected from the group consisting of hydrogen, halogen, —CHF2, —CF3, —NO2, —CN, —C(O)R″, —C(O)OR″, —SO2R″, —C(O)NR″2, —C(O)N(OR″)R″ and
- R″ is hydrogen or an optionally substituted group selected from:
- (a) C1-6 alkyl or C1-6 cycloalkyl;
- (b) a 3-8 membered saturated or partially unsaturated cycloalkyl ring formed from two R″;
- (c) a 3-8 membered saturated or partially unsaturated heterocycloalkyl ring formed from two R″ having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- (d) phenyl; and
- (e) a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- X is chosen from O, S, S(O), SO2, —C2, and NR″;
- Y is chosen from O, S, and NR2;
- R2 is selected from the group consisting of
- (a) hydrogen, —OH, —C(O)R″, —O(CH2)0-4R″, —(CH2)0-4C(O)R″, —(CH2)0-4C(O)OR″, —NR″2, —(CH2)0-4C(O)NR″2, —(CH2)0-4S(O)R″, —(CH2)0-4S(O)2R″, or —N(OR″)R″; and
- (b) an optionally substituted group selected from
- (1) C1-6 alkyl;
- (2) 3-8 membered saturated or partially unsaturated cycloalkyl ring;
- (3) 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- (4) phenyl, and
- (5) a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- A is nitrogen or a carbon atom optionally substituted by H or an R′ substituent;
- B is a ring selected from
- (a) a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;
- (b) phenyl;
- (c) an 8-10 membered bicyclic aryl ring;
- (d) a 3-8 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- (e) a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
- (f) an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- wherein B is optionally substituted with one or more R′ substituents;
- R′ is chosen from
- (a) hydrogen, halogen, —CHF2, —CF3, —NO2, —CN, —OH, —C(O)R″, —C(O)OR″, —SO2R″, —C(O)NR″2, —C(O)N(OR″)R″ and
- and
-
- (b) an optionally substituted group selected from
- (1) C1-6 alkyl;
- (2) a 3-8 membered saturated or partially unsaturated cycloalkyl ring;
- (3) a 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- (4) phenyl; and
- (5) a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- (b) an optionally substituted group selected from
- R3 is chosen from
- (a) hydrogen, halogen, —O(CH2)0-4R″, —(CH2)0-4C(O)R″, and
- (b) an optionally substituted group selected from
- (1) C1-6 alkyl,
- (2) a 3-8 membered saturated or partially unsaturated cycloalkyl ring,
- (3) a 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,
- (4) phenyl, and
- (5) a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- R4 is selected from the group consisting of
- (a) hydrogen, —C(O)R″, —O(CH2)0-4R″, —(CH2)0-4C(O)R″, —(CH2)0-4C(O)OR″, —NR″2, —(CH2)0-4C(O)NR″2, —(CH2)0-4S(O)R″, —(CH2)0-4S(O)2R″, —N(OR″)R″; and
- (b) an optionally substituted group selected from
- (1) C1-6 alkyl,
- (2) a 3-8 membered saturated or partially unsaturated cycloalkyl ring,
- (3) a 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,
- (4) phenyl, and
- (5) a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
- In another aspect the invention relates to methods for inhibiting monocarboxylate transport. The methods comprise contacting a monocarboxylate transporter with an effective amount of a compound described herein.
- In another aspect, the invention relates to a method for treating a disorder associated with monocarboxylate transport comprising administering a compound described herein. Such disorders include cancer and other neoplastic disorders, inflammatory diseases, disorders of abnormal tissue growth, metabolic disorders, diabetes, obesity, malaria, and tissue and organ rejection.
- In certain embodiments, the present invention relates to a compound of formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
-
- n is 0, 1, or 2;
- W is a bond, C═O, or SO2;
- Z is selected from O, S, N—CN, and NR″;
- R1 is independently selected from the group consisting of hydrogen, halogen (Br, F, I, Cl), —CHF2, —CF3, —NO2, —CN, —C(O)R″, —C(O)OR″, —SO2R″, —C(O)NR″2, —C(O)N(OR″)R″ and
- R″ is hydrogen or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- X is either O, S, S (O), S (O)2, or NR″;
- Y is either O, S, or NR2;
- R2 is independently selected from the group of hydrogen, —OH, —C(O)R, —O(CH2)0-4R″, —(CH2)0-4C(O)R″, —(CH2)0-4C(O)OR″, —NR″2, —(CH2)0-4C(O)NR″2, —(CH2)0-4S(O)R″, —(CH2)0-4S(O)2R″, —N(OR″)R″, or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- A is a nitrogen (N) or a carbon (C) atom optionally substituted by H or R′ substituent;
- B is a ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aryl ring, a 3-8 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein B is optionally substituted with one or more R′ substituents;
- R′ is hydrogen, halogen (Br, F, I, Cl), —CHF2, —CF3, —NO2, —CN, —OH, —C(O)R″, —C(O)OR″, —SO2R″, —C(O)NR″2 and —C(O)N(OR″)R″;
- or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- R3 is hydrogen, halogen (Br, F, I, Cl), —O(CH2)0-4R″, —(CH2)0-4C(O)R″, or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- R4 is independently selected from the group of hydrogen, —C(O)R″, —O(CH2)0-4R″, —(CH2)0-4C(O)R″, —(CH2)0-4C(O)OR″, —NR″2, —(CH2)0-4C(O)NR″2, —(CH2)0-4S(O)R″, —(CH2)0-4S(O)2R″, —N(OR″)R″, or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Compounds described herein and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with abnormal cellular responses triggered by altered cellular metabolism. Such diseases, disorders, or conditions include those described below.
- Compounds provided by this invention are also useful for the study of monocarboxylate transport modulation in biological and pathological phenomena; the study of intracellular and intercellular signal transduction pathways mediated by lactate and other monocarboxylates, and the comparative evaluation of new monocarboxylate transport modulatorsThe novel features of the present invention will become apparent to those of skill in the art upon examination of the following detailed description of the invention. It should be understood, however, that the detailed description of the invention and the specific examples presented, while indicating certain embodiments of the present invention, are provided for illustration purposes only because various changes and modifications within the spirit and scope of the invention will become apparent to those of skill in the art from the detailed description of the invention and claims that follow.
- As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
- Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by reference herein for its exemplary chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 5.09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.
- Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers or enantiomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.
- Generally, reference to a certain element such as hydrogen or H is meant (if appropriate) to include all isotopes of that element, for example, deuterium and tritium for hydrogen.
- The term “alkyl” as used herein means a straight- or branched-chain hydrocarbon having from one to eight carbon atoms, and includes, for example, and without being limited thereto, methyl, ethyl, propyl, isopropyl, t-butyl and the like. Substituted alkyl includes, for example, and without being limited thereto, haloalkyl, hydroxyalkyl, cyanoalkyl, and the like. This is applied to any of the groups mentioned herein, such as substituted “alkenyl”, “alkynyl”, “aryl”, etc.
- The term “alkenyl” as used herein means a straight- or branched-chain aliphatic hydrocarbon having at least one double bond. The alkene may have from two to eight carbon atoms, and includes, for example, and without being limited thereto, ethenyl, 1-propenyl, 1-butenyl and the like. The term “alkenyl” encompass radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
- The term “alkynyl” as used herein means a straight- or branched-chain aliphatic hydrocarbon having at least one triple bond. The alkyne may have from two to eight carbon atoms, and includes, for example, and without being limited thereto, 1-propynyl (propargyl), 1-butynyl and the like.
- The term “cycloalkyl” as used herein means an aliphatic carbocyclic system (which may be unsaturated) containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. In one aspect, the ring(s) may have from three to seven carbon atoms, and includes, for example, and without being limited thereto, cyclopropyl, cyclohexyl, cyclohexenyl and the like.
- The term “heterocycloalkyl” as used herein means a heterocyclic system (which may be unsaturated) having at least one heteroatom selected from N, S and/or O and containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. In one aspect, the ring(s) may have a three- to seven-membered cyclic group and includes, for example, and without being limited thereto, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.
- The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.
- The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.
- The term “alkoxy” as used herein means a straight- or branched-chain oxygen-containing hydrocarbon; in one aspect, having from one to eight carbon atoms and includes, for example, and without being limited thereto, methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
- The term “halo” or “halogen” includes, for example, and without being limited thereto, fluoro, chloro, bromo, and iodo, in both radioactive and non-radioactive forms.
- The term “alkylene” as used herein means a difunctional branched or unbranched saturated hydrocarbon; in one aspect, having one to eight carbon atoms, and includes, for example, and without being limited thereto, methylene, ethylene, n-propylene, n-butylene and the like.
- The term “aryl”, alone or in combination, as used herein means a carbocyclic aromatic system containing one or more rings. In particular embodiments, aryl is one, two or three rings. In one aspect, the aryl has five to twelve ring atoms. The term “aryl” encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. The “aryl” group may have 1 to 4 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
- The term “heteroaryl”, alone or in combination, as used herein means an aromatic system having at least one heteroatom selected from N, S and/or O and containing one or more rings. In particular embodiments, heteroaryl is one, two or three rings. In one aspect, the heteroaryl has five to twelve ring atoms. The term “heteroaryl” encompasses heteroaromatic groups such as triazolyl, imidazolyl, pyrrolyl, tetrazolyl, pyridyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl, thiazolyl and the like. The “heteroaryl” group may have 1 to 4 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
- It is understood that substituents and substitution patterns on the compounds of the invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure results.
- As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
- Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH2)0-4Ro; —(CH2)0-40Ro; —O(CH2)0-4Ro, —O—(CH2)0-4C(O)ORo;)—(CH2)0-4CH(ORo)2, —(CH2)0-4SRo; —(CH2)0-4Ph, which may be substituted with Ro; —(CH2)0-4O(CH2)0-1Ph which may be substituted with Ro; —CH═CHPh, which may be substituted with Ro; —(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with Ro; —NO2; —CN; —N3; —(CH2)0-4N(Ro)2; —(CH2)0-4N(RoC(O)Ro;)—N(Ro)C(S)Ro; —(CH2)0-4N(Ro)C(O)NRo 2; —N(Ro)C(S)NRo 2; —(CH2)0-4N(Ro)C(O)ORo; —N(Ro)N(Ro)C(O)Ro; —N(Ro)N(Ro)C(O)NRo 2; —N(Ro)N(Ro)C(O)ORo; —(CH2)0-4C(O)Ro; —C(S)Ro; —(CH2)0-4C(O)ORo; —(CH2)0-4C(O)SRo; —(CH2)0-4C(O)OSiRo 3; —(CH2)0-4OC(O)Ro; —6OC(O)(CH2)0-4SR—, SC(S)SRo; —(CH2)0-4SC(O)Ro; —(CH2)0-4C(O)NRo 2; —C(S)NRo 2; —C(S)SRo; —SC(S)SRo, —(CH2)0-40C(O)NRo 2; —C(O)N(ORo)Ro; —C(O)C(O)Ro; —C(O)CH2C(O)Ro; —C(NORo)Ro; —(CH2)0-4SSRo; —(CH2)0-4S(O)2Ro; —(CH2)0-4S(O)2ORo; —(CH2)0-4OS(O)2Ro; —S(O)2NRo 2; —(CH2)0-4S(O)Ro; —N(Ro)S(O)2NRo 2; —N(Ro)S(O)2Ro; —N(ORo)Ro; —C(NH)NRo 2; —P(O)2Ro; —P(O)Ro 2; —OP(O)o 2; —OP(O)(ORo 2; SiRo 3; —(C1-4 straight or branched)alkylene)O—N(Ro)2; or —(C1-4 straight or branched alkylene)C(O)O—N(Ro)2, wherein each Ro may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, —CH2Ph, —O(CH2)0-1Ph, —CH2-(5-6 membered heteroaryl ring), or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Ro, taken together with their intervening atom(s), form a 3-12- membered saturated, partially unsaturated, or aryl mono—or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
- Suitable monovalent substituents on Ro (or the ring formed by taking two independent occurrences of Ro together with their intervening atoms), are independently halogen, —(CH2)0-2R⋅, -(haloR⋅), —(CH2)0-2OH, —(CH2)0-2OR⋅, —(CH2)0-2CH(OR108)2; —O(haloR⋅), —CN, —N3, —(CH2)0-2C(O)R⋅, —(CH2)0-2C(O)OH, —(CH2)0-2C(O)OR⋅, —(CH2)0-2SR⋅, —(CH2)0-2SH, —(CH2)0-2NH2, —(CH2)0-2NHR⋅, —(CH2)0-2NR⋅ 2, —NO2, —SiR⋅ 3, —C(O)SR⋅, —(C1-4 straight or branched alkylene)C(O)OR⋅, or —SSR⋅ wherein each R⋅ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of Ro include ═O and ═S.
- Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)2R*, ═NR*, ═NOR*, —O(C(R*2))2-3O—, or —S(C(R*2))2-3S—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR*2)2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Suitable substituents on the aliphatic group of R* include halogen, —R⋅, -(haloR⋅), —OH, —OR⋅, —O(haloR⋅), —CN, —C(O)OH, —C(O)OR⋅, —NH2, —NHR⋅, —NR⋅ 2, or —NO2, wherein each R⋅ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R†, —NR† 2, —C(O)R†, —C(O)OR†, —C(O)C(O)R\, —C(O)CH2C(O)R\, —S(O)2R†, —S(O)2NR†, —C(S)NR† 2, —C(NH)NR† 2, or —N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono—or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Suitable substituents on the aliphatic group of R† are independently halogen, —R⋅, —(haloR⋅), —OH, —OR⋅, —O(haloR⋅), —CN, —C(O)OH, —C(O)OR⋅, —NH2, —NHR⋅, —NR⋅ 2, or —NO2, wherein each R⋅ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)o_iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p—toluenesulfonate, undecanoate, valerate salts, and the like.
- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
- Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
- The term “pharmaceutically acceptable salt” means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients. In some embodiments, exemplary inorganic acids which form suitable salts include, but are not limited thereto, hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
- A “pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formula I or any of its intermediates. Illustrative inorganic bases which form suitable salts include, but are not limited thereto, lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia. The selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
- Acid addition salts of the compounds of Formula I are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid. Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are base addition salts (such as sodium, potassium and ammonium salts), solvates and hydrates of compounds of the invention. The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, well known to one skilled in the art.
- The term “stereoisomers” is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
- The term “treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to inhibit or slow the appearance of symptoms of the named disorder or condition. The term “therapeutically effective amount” means an amount of the compound which is effective in treating or lessening the severity of one or more symptoms of a disorder or condition.
- The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is pharmaceutically acceptable oil typically used for parenteral administration.
- When introducing elements disclosed herein, the articles “a”, “an”, “the”, and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “having”, “including” are intended to be open-ended and mean that there may be additional elements other than the listed elements.
- According to one aspect, the present invention relates to a compound of formula II,
-
- or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the following structure:
-
- or a pharmaceutically acceptable salt thereof, wherein:
- n is 0, 1, or 2;
- W is a bond, C═O, or SO2;
- Z is selected from O, S, N—CN, and NR″;
- R1 is independently selected from the group consisting of hydrogen, halogen (Br, F, I, Cl), —CHF2, —CF3, —NO2, —CN, —C(O)R″, —C(O)OR″, —SO2R″, —C(O)NR″2, and —C(O)N(OR″)R″,
- R″ is hydrogen or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- X is either O, S, S(O), SO2, or NR″;
- Y is either O, S, or NR2;
- R2 is independently selected from the group of hydrogen, —OH, —C(O)R″, —O(CH2)0-4R″, —(CH2)0-4C(O)R″, —(CH2)0-4C(O)OR″, —NR″2, —(CH2)0-4C(O)NR″ 2, —(CH2)0-4S(O)R″, —(CH2)0-4S(O)2R″, —N(OR″)R″, or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- A is a nitrogen (N) or a carbon (C) atom optionally substituted by H or R′ substituent;
- B is a ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aryl ring, a 3-8 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein B is optionally substituted with one or more R′ substituents;
- R′ is hydrogen, halogen (Br, F, I, Cl), —CHF2, —CF3, —NO2, —CN, —OH, —C(O)R″, —C(O)OR″, —SO2R″, —C(O)NR″2 and —C(O)N(OR″)R″;
- or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- R3 is hydrogen, halogen (Br, F, I, Cl), —O(CH2)0-4R″, —(CH2)0-4C(O)R″, or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- R4 is independently selected from the group of hydrogen, —C(O)R″, —O(CH2)0-4R″, —(CH2)0-4C(O)R″, —(CH2)0-4C(O)OR″, —NR″2, —(CH2)0-4C(O)NR″2, —(CH2)0-4S(O)R″, —(CH2)0-4S(O)2R″, —N(OR″)R″, or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
- Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl.
- In some embodiments, the compound has the following structure III:
-
- or a pharmaceutically acceptable salt thereof, wherein:
- n is 0, 1, or 2;
- W is a bond, C═O, or SO2;
- Z is selected from O, S, N—CN, and NR″;
- R1 is independently selected from the group consisting of hydrogen, halogen (Br, F, I, Cl), —CHF2, —CF3, —NO2, —CN, —C(O)R″, —C(O)OR″, —SO2R″, —C(O)NR″2, and —C(O)N(OR″)R″,
- R″ is hydrogen or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- X is either O, S, S(O), SO2, or NR″;
- Y is either O, S, or NR2;
- R2 is independently selected from the group of hydrogen, —OH, —C(O)R, —O(CH2)0-4R″, —(CH2)0-4C(O)R″, —(CH2)0-4C(O)OR″, —NR″2, —(CH2)0-4C(O)NR″2, —(CH2)0-4S(O)R″, —(CH2)0-4S(O)2R″, —N(OR″)R″, or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- A is a nitrogen (N) or a carbon (C) atom optionally substituted by H or R′ substituent;
- B is a ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aryl ring, a 3-8 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein B is optionally substituted with one or more R′ substituents;
- R′ is hydrogen, halogen (Br, F, I, Cl), —CHF2, —CF3, —NO2, —CN, —OH, —C(O)R″, —C(O)OR″, —SO2R″, —C(O)NR″2 and —C(O)N(OR″)R″,
- or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- R3 is hydrogen, halogen (Br, F, I, Cl), —O(CH2)0-4R″, —(CH2)0-4C(O)R″, or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- R4 is independently selected from the group of hydrogen, —C(O)R″, —O(CH2)0-4R″, —(CH2)0-4C(O)R″, —(CH2)0-4C(O)OR″, —NR″2, —(CH2)0-4C(O)NR″2, —(CH2)0-4S(O)R″, —(CH2)0-4S(O)2R″, —N(OR″)R″, or an optionally substituted group selected from C1-6 alkyl, 3-8 membered saturated or partially unsaturated cycloalkyl ring, 3-8 membered saturated or partially unsaturated heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
- Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl.
- In one embodiment of structures I, II and III, Z is oxygen. In another embodiment, A is carbon. In other embodiment, n is equal to 0. In some embodiments, R3 is hydrogen, Y is oxygen, and R2 is hydrogen. In a further embodiment, the base addition salt is formed from sodium, potassium, magnesium, calcium.
- In some embodiments, the compound has the following structure:
- or a pharmaceutically acceptable salt thereof, wherein each of R1, R4, X, and Ar is as defined above and described herein. In some embodiments, R1 is a —C(O)Ro. In some embodiments, X is a methylene or substituted methylene.
- In some embodiments, the compound has the following structure:
- wherein each of R″, Ar, and R4 is as defined above and described herein.
- In some embodiments, R″ is an amine (e.g., azetidine). In some embodiments, Ar is substituted phenyl (e.g. trifluoromethyl phenyl) and the other is substituted pyrazole (e.g. dimethyl pyrazole). In some embodiments, R4is substituted or unsubstituted alkyl (e.g., isopropyl, isobutyl, cyclopropyl).
- In some embodiments, the compound is selected from;
- In some embodiments, the compound has the following structure:
- wherein each of R1, R4, X, n, W, and Ar is as defined above and described herein. In one embodiment, X is nitrogen. In another embodiment, n is equal to 1. In a further embodiment, W is a bond, and a base addition salt is formed from sodium, potassium, magnesium, or calcium.
- In some embodiments, the compound has the following structure:
- wherein each of R″, R1, Ar, and R4 is as defined above and described herein. In some embodiments, R″ is an alkyl (e.g., methyl). In some embodiments, R1 is a halogen (e.g., fluoro). In some embodiments, R1 is an amide (e.g., azetidino amide). In some embodiments, Ar is unsubstituted or substituted phenyl (e.g. p-chlorophenyl). In some embodiments, R4 is substituted or unsubstituted alkyl (e.g., isopropyl, isobutyl, ethyl, benzyl).
- In some embodiments, the compound is selected from:
- In some embodiments, the compound has the following structure:
-
- wherein each of R″ , Ar, W, and R4 is as defined above and described herein. In some embodiments, R″ is an alkyl (e.g., methyl). In some embodiments, Rl is a halogen (e.g., fluoro). In some embodiments, W is a carboxy (e.g., carbonyl). In some embodiments, Ar is unsubstituted or substituted phenyl (e.g. phenyl). In some embodiments, R4 is substituted or unsubstituted alkyl (e.g., isobutyl, benzyl).
- In some embodiments, the compound is selected from;
- In some embodiments, the compound has the following structure:
-
- wherein each of R1, R4, X, n, W, B, and Ar is as defined above and described herein. In one embodiment, X is nitrogen. In another embodiment, n is equal to 1. In a further embodiment, W is a bond, and a base addition salt is formed from sodium, potassium, magnesium, or calcium.
- In some embodiments, the compound has the following structure:
-
- wherein each of R″, R1, B, and R4 is as defined above and described herein. In some embodiments, R″ is an alkyl (e.g., methyl). In some embodiments, R1 is a halogen (e.g., fluoro). In some embodiments, B is unsubstituted or substituted cycloalkyl (e.g. cyclohexyl, piperidinyl). In some embodiments, R4 is substituted or unsubstituted alkyl (e.g., isopropyl, isobutyl, ethyl, benzyl).
- In some embodiments, the compound is selected from:
- In one aspect, the invention relates to a method of treating a neoplastic or inflammatory or metabolic disorder in a subject, comprising administering a pharmaceutically effective amount of a compound or composition described herein.
- Also provided herein are methods of treating a disease associated with expression or activity of MCT1, MCT2, MCT3, MCT4, CD147, NFkB, p53 in a subject comprising administering to the patient a therapeutically effective amount of a compound described herein. For example, provided herein are methods of treating various cancers in mammals specifically including humans, dogs, cats, and farm animals, including hematologic malignancies (leukemias, lymphomas, myelomas, myelodysplastic and myeloproliferative syndromes) and solid tumors (carcinomas such as prostate, breast, lung, colon, pancreatic, renal, brain, —CNS, skin, cervical, ovarian as well as soft tissue and osteo- sarcomas, and stromal tumors), inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriatic arthritis, multiple scelorisis, systemic lupus, systemic sclerosis, vasculitis syndromes (small, medium and large vessel),atherosclerosis, psoriasis and other dermatological inflammatory disorders (such as pemphigous, pemphigoid, allergic dermatitis),and urticarial syndromes comprising administering a compound represented by formula I.
- Also provided are compounds represented by formula I for use in therapy and/or for the manufacture of a medicament for the treatment of a disease associated with expression or activity of MCT1, MCT2, MCT3, MCT4, CD147, NFkB, p53 in a subject.
- The compounds and compositions described herein may be administered intravenously, intraperitoneally, or orally.
- In some embodiments, the present invention provides a compound selected from:
-
- 7-(benzyl(methyl)amino)-6-fluoro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 7-(benzyl(methyl)amino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 7-(benzyl(methyl)amino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1-benzyl-6-fluoro-743-methoxybenzyl)(methyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 6-fluoro-1-isobutyl-7-(methyl(thiophen-2-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 6-(azetidine-1-carbonyl)-1-isobutyl-4-oxo-7-(2-(trifluoromethyl)benzyl)-1,4-dihydroquinoline-3-carboxylic acid
- 6-(azetidine-1-carbonyl)-1-isopropyl-4-oxo-7-(2-(trifluoromethyl)benzyl)-1,4-dihydroquinoline-3-carboxylic acid
- 6-(azetidine-1-carbonyl)-1-cyclopropyl-4-oxo-7-(2-(trifluoromethyl)benzyl)-1,4-dihydroquinoline-3-carboxylic acid
- 6-(azetidine-1-carbonyl)-7-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 7-((4-chlorobenzyl)(methyl)amino)-6-fluoro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 6-fluoro-1-isobutyl-4-oxo-7-((3-(trifluoromethyl)benzyl)amino)-1,4-dihydroquinoline-3-carboxylic acid
- 6-fluoro-1-isobutyl-743-methoxybenzyl)(methyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 6-fluoro-1-isobutyl-7-(N-methylbenzamido)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 1-benzyl-6-fluoro-7-(N-methylbenzamido)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 6-fluoro-1-isobutyl-7-(methyl((1-methylpiperidin-4-yl)methyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 6-fluoro-1-isobutyl-7-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 7-((cyclohexylmethyl)(methyl)amino)-6-fluoro-1-i sobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 6-fluoro-7-((3-fluorobenzyl)(methyl)amino)-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 6-fluoro-1-isopropyl-7-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 6-fluoro-74(4-fluorobenzyl)(methyl)amino)-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- bis(trifluoromethyl)benzyl)(methyl)amino)-6-fluoro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 6-fluoro-1-isobutyl-7-(methyl(thiazol-5-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 6-fluoro-1-isobutyl-7-(methyl(oxazol-5-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
- 6-fluoro-7-(N-methylbenzamido)-4-oxo-1-(pyridin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically-acceptable salt thereof.
- In one aspect, the invention relates to a composition comprising a compound described herein, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions will normally be an amount effective to measurably inhibit monocarboxylate transport, in a biological sample or in a patient. However, compositions containing a fraction of the effective amount may be employed for multiple dosing. In some embodiments, a composition of this invention is formulated for oral administration, intravenous, subcutaneous, intraperitoneal or dramatological application to a patient.
- The term “patient”, as used herein, means an animal. In some embodiments, the animal is a mammal. In certain embodiments, the patient is a veterinary patient (i.e., a non-human mammal patient). In some embodiments, the patient is a dog. In other embodiments, the patient is a human.
- Compounds and compositions described herein are generally useful for the inhibition of monocarboxylate transport. The activity of a compound may be assayed in vitro, in vivo or in a cell line. Detailed conditions for assaying a compound utilized as an inhibitor of monocarboxylate transport are set forth in the Examples below. The compounds and compositions described herein can be administered to cells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., in vivo, to treat and/or diagnose a variety of disorders, including those described herein below.
- As used herein, the term “treat” or “treatment” is defined as the application or administration of a compound, alone or in combination with, a second compound to a subject, e.g., a patient, or application or administration of the compound to an isolated tissue or cell, e.g., cell line, from a subject, e.g., a patient, who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder, one or more symptoms of the disorder or the predisposition toward the disorder (e.g., to reduce at least one symptom of the disorder or to delay onset of at least one symptom of the disorder).
- As used herein, an amount of a compound effective to treat a disorder, or a “therapeutically effective amount” refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.
- As used herein, “a prophylactically effective amount” of the compound refers to an amount effective, upon single- or multiple-dose administration to the subject, in reducing or delaying the occurrence of the onset or recurrence of a disorder or a symptom of the disorder.
- As used herein, the term “subject” is intended to include human and non-human animals. Exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein or a normal subject. The term “non-human animals” of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, cow, pig, etc, and companion animals (dog, cat, horse etc).
- Provided compounds are inhibitors of monocarboxylate transport and are therefore useful for treating one or more disorders associated with activity of monocarboxylate transport. Thus, in certain embodiments, the present invention provides a method for treating a monocarboxylate transport-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.
- The term “monocarboxylate transport-mediated” disorder or condition, as used herein, means any disease or other deleterious condition in which monocarboxylate transport is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which monocarboxylate transport is known to play a role. Specifically, the present invention relates to a method of treating or lessening the severity of a proliferative disorder. Disorders are set forth in detail below.
- Neoplastic Disorders
- A compound or composition described herein can be used to treat a neoplastic disorder. A “neoplastic disorder” is a disease or disorder characterized by cells that have the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. Exemplary neoplastic disorders include: carcinoma, sarcoma, metastatic disorders (e.g., tumors arising from prostate, colon, lung, breast, cervical, ovarian, liver, melanoma, brain, —CNS, head and neck, osteosarcoma, gastrointestinal, pancreatic, hematopoietic neoplastic disorders, e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders, and metastatic tumors. Prevalent cancers include: breast, prostate, colon, lung, liver, and pancreatic cancers. Treatment with the compound may be in an amount effective to ameliorate at least one symptom of the neoplastic disorder, e.g., reduced cell proliferation, reduced tumor mass, etc.
- The disclosed methods are useful in the treatment of cancer, including for example, solid tumors, soft tissue tumors, and metastases thereof, as well as in familial cancer syndromes such as Li Fraumeni Syndrome, Familial Breast-Ovarian Cancer (BRCA1 or BRAC2 mutations) Syndromes, and others. The disclosed methods are also useful in treating non-solid cancers. Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the various organ systems, such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary (e.g., renal, urothelial, or testicular tumors) tracts, pharynx, prostate, and ovary. Exemplary adenocarcinomas include colorectal cancers, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, and cancer of the small intestine. Exemplary cancers described by the National Cancer Institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS- Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-CeIl; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T-Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor. Metastases of the aforementioned cancers can also be treated in accordance with the methods described herein.
- Cancer Combination Therapies
- In some embodiments, a compound described herein is administered together with an additional cancer treatment. Exemplary cancer treatments include, for example: chemotherapy, targeted therapies such as antibody therapies, kinase inhibitors, immunotherapy, cancer metabolism therapies, hormonal therapy, and anti-angiogenic therapies.
- Anti-Angiogenic Therapy
- Compounds and methods described herein may be used to treat a disease or disorder associated with angiogenesis. Diseases associated with angiogenesis include cancer, cardiovascular diseases and mascular degeneration. Angiogenesis is the physiological processes involving the growth of new vessels from pre-existing blood vessels. Angiogenesis is the normal and vital process in growth and development, as well as in wound healing and in granular tissue. However, it is also a fundamental step in the transition of tumors from a dormant state to a malignant one. Angiogenesis may be a target for combating diseases characterized by either poor vascularization or abnormal vasculature. Application of specific compounds that may inhibit the creation of new blood vessels in the body may help combat such diseases. The presence of blood vessels where there should be none may affect the normal properties of a tissue, increasing the likelihood of failure. The absence of blood vessels in a repairing or otherwise metabolically active tissue may inhibit repair or other essential functions. Several diseases such as ischemic chronic wounds are the results of failure or insufficient blood vessel formation and may be treated by a local expansion of blood vessels, thus bringing new nutrients to the site, facilitating repair. Other diseases such as age-related macular degeneration may be created by a local expansion of blood vessels, interfering with normal physiological processes.
- Vascular endothelial growth factor (VEGF) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network. Upregulation of VEGF is a major component of the physiological response to exercise and its role in angiogenesis is suspected to be a possible treatment for vascular injuries. In vitro studies clearly demonstrated that VEGF is a potent stimulator of angiogenensis because, in the presence of this growth factor, plated endothelial cells will proliferate and migrate, eventually forming tube structures resembling capillaries.
- Tumors induce blood vessel growth by secreting various growth factors (e.g. VEGF). Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which may supply required nutrients allowing for tumor expansion. Angiogenesis therefore represents an attractive target for the treatment of cancer and cardiovascular diseases. It is a potent physiological process that underlies the natural manner in which our bodies responds to a diminution of blood supply to vital organs, namely the production of new collateral vessels to overcome the ischemic insult. Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In wet macular degeneration, VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes edema, blood and other retinal fluids leak into the retina causing loss of vision. Antiangiogenic therapy can include kinase inhibitors targeting vascular endothelial growth factor (VEGF) such as sutinib, sorafenib, or monoclonal antibodies or recerptor “decoys” to VEGF or VEGF-Trap or thalidomide or its analogs (lenalidimide, pomalidomide), or agents targeting non-VEGF angiogenic targets such as fibroblast growth factor (FGF), angiopoietins, or angiostatin, or ensostatin.
- Immunosuppression
- The body immune system detects foreign objects and organisms such as bacteria, virus, and other pathogens, and protects the body by eliminating those harmful matters. Sometimes, those immune system responses against foreign pathogens or tissues become more harmful to the host, for example, allergies to food and extrinsic antigens such as pollen and respiratory diseases such as asthma. In addition, strong responses against transplant tissues or organs occur, leading to the rejection of them. In such cases, immunosuppressive drugs are needed to avoid those complications. Additionally, the body's immune system does not exert responses against self-tissues or self-antigens under normal circumstances. However, in some cases, body exerts a strong immune response against self-tissues aggressively leading to a variety of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, type I diabetes, etc. Most immune responses are initiated and controlled by T helper lymphocytes, which respond to antigens.
- A number of immunosuppressive therapies have been developed over the last decades. These include rapamycin, which disrupts the cytokine such as IL-2-driven T-cell proliferation by interefering with TOR (Target of Rapamycin) function. However, rapamycin has been shown to cause significant side effects including hyperlipidemia (Hong et al, Semin. Nephrol., 10(2); 108-125, 2000).
- MCTs may act as biomarkers and compounds and compositions described herein may also be used to treat selectively sub-population of patients who express either MCT1 or MCT4 or both. It is known that a patient's response to a drug may be dependent upon patient's genetic profile and/or the type of the disease. It has been demonstrated that MCT4 is a biomarker that predicts poor overall survival of aggressive triple negative breast cancer patients.
- Abbreviations:
- atm Atmosphere
- aq. Aqueous
- BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
- Boc tert-butoxycarbonyl
- CDI N,N′-Carbonyldiimidazole
- DCC N,N-Dicyclohexylcarbodiimide
- DCM Dichloromethane
- DBU Diaza(1,3)bicyclo[5.4.0]undecane
- DEA N,N-Diisopropyl ethylamine
- DIBAL-H Diisobutylaluminium hydride
- DIC N,N′-Diisopropylcarbodiimide
- DMAP N,N-Dimethyl-4-aminopyridine
- DMF Dimethylformamide
- DMSO Dimethylsulfoxide
- DPPF Diphenylphosphinoferrocene
- EA Ethyl acetate
- EDCI N[3-(dimethylamino)propyl]N′-ethylcarbodiimide hydrochloride
- EDC 1-Ethyl-3 -(3 -dimethyl aminopropyl)carbodiimide
- Et2O Diethylether
- EtOAc Ethyl acetate
- EtOH Ethanol
- EtI Iodoethane
- Et Ethyl
- Fmoc 9-fluorenylmethyloxycarbonyl
- h hour(s)
- HetAr Heteroaryl
- HOBt N-Hydroxybenzotriazole
- HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
- HPLC High performance liquid chromatography
- LAH Lithium aluminium hydride
- LCMS HPLC mass spec
- MCPBA m-Chlorbenzoic acid
- MeCN Acetonitrile
- MeOH Methanol
- min Minutes
- MeI Iodomethane
- MeMgCl Methyl magnesium chloride
- Me Methyl
- MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carb oxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
- MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- n-BuLi 1-Butyllithium
- NaOAc Sodium acetate
- NMR Monocarboxylate magnetic resonance
- NMP N-Methyl pyrrolidinone
- nBuLi 1-Butyl lithium
- o.n. Over night
- Ph phenyl
- RT, rt, r.t. Room temperature
- TEA Triethylamine
- THF Tetrahydrofurane
- nBu normal Butyl
- OMs Mesylate or methane sulfonate ester
- OTs Tosylate, toluene sulfonate or 4-methylbenzene sulfonate ester
- PCC Pyridinium chlorochromate
- PPTS Pyridinium p-toluenesulfonate
- TBAF Tetrabutylammonium fluoride
- pTsOH p-Toluenesulfonic acid
- SPE Solid phase extraction (usually containing silica gel for mini-chromatography)
- sat. Saturated
- PG Protecting group
- mins minutes
- Throughout the following description of such processes it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis”, T. W. Green, P. G. M. Wuts, Wiley-Interscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to the one skilled in the art of organic synthesis. Examples of transformations are given below, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions on other suitable transformations are given in “Comprehensive Organic Transformations —A Guide to Functional Group Preparations” R. C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis”, Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by the one skilled in the art. The definitions of substituents and groups are as in formula I except where defined differently. The term “room temperature” and “ambient temperature” shall mean, unless otherwise specified, a temperature between 16 and 25° C. The term “reflux” shall mean, unless otherwise stated, in reference to an employed solvent a temperature at or above the boiling point of named solvent.
- General Synthetic Methods
- Several general methods for preparing compounds of Formula I are illustrated in the following Schemes and Examples. Starting materials and the requisite intermediates are in some cases commercially available or can be prepared according to literature procedures (Bioorg. Med. Chem. 16, 2008, 9487-9497; Bioorg. Med. Chem. 16, 2008, 10031-10310; Synthetic Comm. 35, 2005, 761-764) or as illustrated herein. In the steps where product was obtained as a mixture of isomers, pure isomers can be easily separated using chromatographic methods in the literature.
- It is understood that the functional groups present in compounds described in the Schemes below can be further manipulated, when appropriate, using the standard functional group transformation techniques available to those skilled in the art, to provide desired compounds described in this invention. Other variations or modifications, which will be obvious to those skilled in the art, are within the scope and teachings of this invention.
- Certain quinolone carboxylic acid compounds of Formula I, wherein the R4 group is an alkyl, B is an aryl or heteroaryl group, and Rl group is hydrogen, fluorine, or optionally substituted carboxylic acid, carboxylic ester, carboxy amides, cyano, etc., can be prepared in accordance with general Scheme 1.
- In Scheme 2, the group Ar is selected from aryl and heteroaryl optionally substituted with one or more substituents and, the X is an alkyl group, and the R4 group is an alkyl, and R1 group is hydrogen, fluorine, or optionally substituted amine, carboxylic acid, carboxylic ester, carboxy amides, cyano, etc., can be prepared in accordance with general Scheme 2.
- In Scheme 3 and Scheme 5, a general method is described for the preparation of certain napthyridone compounds of Formula I, wherein the R4 group is an alkyl.
- In Scheme 4, a general method is described for the preparation of certain pyrazopyridone compounds of Formula I, wherein the R4 group is an alkyl, and R1 group is hydrogen, fluorine, or optionally substituted carboxylic acid, carboxylic ester, carboxy amides, cyano, etc.
- In a similar manner the following compounds were synthesized:
-
-
- In a 250 mL, 3-neck round-bottomed flask, 3-Chloro-4-fluoroaniline (20 g, 137.4 mmol) was added with toluene (100 mL). To this reaction mixture, diethyl-2-(ethoxymethylene) malonate (29.7 g, 137.4 mmol) was added at 25° C. The reaction mixture was heated at reflux under stirring for 1 h, then cooled to 30° C. and added water (150 mL). The mixture was extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 40 g of crude product which was triturated with minimum hexanes to obtain diethyl-2-((3-chloro-4-fluorophenylamino) methylene)malonate (1) 36 g; Yield (50.1%); 1H NMR (400 MHz, DMSO-d6): δ 10.61 (d, J=12.8, 1H), 8.29 (d, J=13.6, 1H), 7.72-7.74 (m, 1H), 7.4-7.42 (m, 2H), 4.12-4.2 (m, 4H), 1.24-1.26 (m, 6H); MS (ESI): 316.1(M+H).
-
- In a 500 mL, 3-neck round-bottomed flask, diphenylether (200 mL) was heated up to 150° C. To this falsk, diethyl 2-{(3-chloro-4-fluorophenylamino)methylene}malonate (1) (36 g, 114.1 mmol) was added. The reaction mixture was stirred at that temperature for 4-5 h. The reaction mixture was then cooled to room temperature, and hexanes (1 L) was added to precipitate the compound. The solid obtain was filtered to obtain 16 g of crude compound. The crude product contained traces of regioisomer formed during cyclization. This product was used for the next step without further purification.
-
- In a 100 mL, 3-neck round-bottomed flask, ethyl 7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (2) (3.8 g, 14.09 mmol) and K2CO3 (9.7 g, 70.45 mmol) were suspended in DMF (30 mL) and the reaction mixture was stirred for 15 min at room temperature. To this mixture, 1-bromo-2-methyl propane (11.6 g, 84.55 mmol) and potassium iodide (0.25 g, 1.409 mmol) were added and the resulting mixture was heated at 80° C. for 24 h. The reaction mixture was cooled and filtered, and the filtrate was evaporated under reduced pressure to obtain 5.3 g of the crude product. The crude product was purified by silica gel column chromatography to obtain 3.3 g of ethyl 7-chloro-6-fluoro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (3); Yield (71.9%); ‘H NMR: (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.21 (d, J=6, 1H), 8.04 (d, J=9.2, 1H), 4.21-4.27 (m, 4H), 2.10-2.13(m, 1H), 1.27-1.31 (m, 3H), 0.88-0.90 (m, 6H); MS (ESI): 326.2(M+H).
-
- In a 100 mL, 3-Neck round-bottomed flask, intermediate (3) (3.3 g, 10.13 mmol) was added with THF :Water (1:1) (10 mL). To this mixture, 2M KOH solution (20 mL) was added dropwise maintaining the temperature at 0° C. The resulting mixture was stirred at room temperature for 2 h and reaction completion was monitored by TLC. The mixture was cooled to 0° C. and acidified to pH 3-4 with 4N HCl. The solid compound obtain was filtered to obtain 2.1 g of the crude product. The product was extracted with EtOAc (50 mL×3) and the combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain, after trituration with minimum hexane, 2 g of 7-chloro-6-fluoro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; Yield (66.6%); ‘H NMR: (400 MHz, CDCl3): δ 14.45 (br s, 1H), 8.69 (s, 1H), 8.26 (d, J=8.4, 1H), 7.65 (d, J=5.2, 1H), 4.07-4.09 (m, 2H), 2.25-2.32 (m, 1H), 1.02-1.05 (m, 6H); MS (ESI): 299.2(M+H).
- Step 5
- In a 25 mL single neck flask, the product from step 4 (3.2 g, 10.77 mmol) and N-benzyl methyl amine (6.5 g, 53.87 mmol) were added and heated at 120° C. for 24 h. The reaction completion was monitored by TLC followed by aqueous work up. The resulting mixture was extracted with EtOAc (50 mL×3) and washed with 5N HCl solution (15 mL×2), dried over anhydrous Na2SO4 to obtain the crude product after solvent evaporation in vacuo. The product was recrystalized from EtOAc (10 vol) to obtain 1.5 g of pure 7-(benzyl(methyl)amino)-6-fluoro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (5a); Yield (36%); 1H NMR (400 MHz, DMSO-d6): δ 15.45 (d, 1H), 6.84-7.90 (m, 8H), 4.70 (s, 2H), 4.25-4.26 (d, 2H), 3.17 (s, 3H), 1.85-1.88 (m, 1H), 0.76-0.78 (d, 6H); MS (ESI): 383.2 (M+H); HPLC: 95.2%.
- Mother liquor remained from the synthesis of Example 1 was concentrated under reduced pressure to obtain the crude 5b. The product was purified by column chromatography (silica gel) to obtain 10 mg of pure 6-(benzyl(methyl)amino)-7-chloro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (5b): Yield, 5%; 1H NMR (400 MHz, DMSO-d6): δ 15.16 (d, 1H), 8.95 (s,1H), 7.28-8.27 (m, 7H), 4.41-4.43 (d, 2H), 4.3 (s, 2H), 2.74 (s, 3H), 2.1-2.2 (m, 1H), 0.88-0.90 (d, 6H); MS (ESI): 399(M+H); HPLC: 93.57%.
-
- In a 25 mL single neck round-bottomed flask, the intermediate 4 (0.5 g, 1.679 mmol) from Example 1 and N-methyl-1-(3-(trifluoromethyl)phenyl)methanamine (1.5 g, 8.39 mmol) were added and heated to 120° C. for 24 h. The reaction was monitored by TLC for completion followed by an aqueous worked up and acidified with 1N HCl to pH 3-4. The aqueous layer was extracted with EtOAc and the organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the crude product which was purified by silica gel column chromatography to provide pure 6-fluoro-1-isobutyl-7-(methyl(3-(trifluoromethyl)benzyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (5), (25 mg); Yield; 3.3%; 1H NMR (400 MHz, DMSO-d6): δ 15.5 (s, 1H), 6.83-8.71 (m, 7H), 4.75 (s, 2H), 4.20 (d, 2H), 3.13 (s, 3H), 1.83-1.86 (m, 1H), 0.74-0.76 (d, 6H); MS(ESI): 451.1(M+H); HPLC: 92.07%.
-
- In a 25 mL single neck round-bottomed flask, the intermediate 4 (1 g, 3.35 mmol) from Example 1 and N-(4-chlorobenzyl)-N-methylamine (2.6 g, 16.7 mmol) were added and the mixture was heated to 120° C. for 24 h. Reaction was monitored by TLC to completion and was added 10 mL water followed by acidification with dil. HCl to pH 3-4. The mixture was extracted with EtOAc (3×50 mL) and the combined organic layer was dried over Na2SO4. The sovent was evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel) to provide the desired product, 7-((4-chlorobenzyl)(methyl)amino)-6-fluoro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (5), 50 mg; Yield (3.5%); 1H NMR (400 MHz, DMSO-d6): δ 15.44 (s, 1H), 6.84-8.70 (m, 7H), 4.66 (s, 2H), 4.24-4.25 (d, 2H), 3.14 (s, 3H), 1.81-1.87 (m, 1H), 0.75-0.77 (d, 6H); MS (ESI): 417.2(M+H); HPLC: 96.35%.
-
- In a 25 mL single neck round-bottomed flask Intermediate 4 (0.5 g, 1.683 mmol) from Example 1 and 3-(trifluoromethyl)-N-benzyl amine (1.47 g, 1.42 mmol) were added and the mixture was heated to 120° C. for 24 h. Reaction was monitored by TLC for completion and the mixture was quenched with 15 mL of water and acidified with 4N HCl to pH 3-4. The aqueous layer was extracted with EtOAc (3×25 mL), and the combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel) to provide the desired product, 6-fluoro-1-isobutyl-4-oxo-7-(3-(trifluoromethyl)benzylamino)-1,4-dihydroquinoline-3-carboxylic acid (5), 25 mg; Yield, 4.0%; 1H NMR (400 MHz, DMSO-d6): δ 15.68 (s, 1H), 7.58-7.87 (m, 7H), 6.51-6.53(d, 1H), 4.71-4.73 (d, 2H), 4.15-4.17 (d, 2H), 1.49 (m, 1H), 0.61-0.63 (d, 6H); MS(ESI): 437.1(M+H); HPLC: 97.48%.
-
- In a closed system, ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (2) (1.4 g, 5.19 mmol) from Example 1 and K2CO3 (3.58 g, 25.92 mmol) were suspended in DMF (14 mL) and the reaction mixture was stirred for 15 min at room temperature. To this reaction mixture, bromoethane (3.39 g, 31.15 mmol) and KI (0.09 g, 0.52 mmol) were added, and the reaction mixture was heated at 80° C. for 24 h. The reaction mixture was then cooled and filtered. The filtrate was partitioned between ethyl acetate and brine solution, and the organic phase was separated and washed with brine solution, and the solvent was removed in vacuo to obtain the crude product which was purified by column chromatography (Silica gel). The fractions containing desired compound were collected together and concentrated under reduced pressure to obtain ethyl 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.2 g); Yield: 77.57%; 1H NMR (400 MHz. CDCl3): δ 8.48 (s, 1H), 8.26 (d, J=9.2, 1H), 7.54 (d, J=5.6, 1H), 4.38-4.43 (m, 2H), 4.21-4.26 (m, 2H), 1.55-1.59 (m, 3H), 1.28-1.43 (m, 3H).
-
- In a 100 mL, 3-neck round-bottomed flask, the intermediate (3) (1.0 g, 3.36 mmol) from Example 6 was charged with THF: Water (4:1) (20 mL). To this reaction mixture, a 2M NaOH solution (6 mL) was added dropwise maintaining the temperature at room temperature. The reaction mixture was stirred at 80° C. for 2 h and then cooled to 0° C. followed by acidification to pH 3-4 by 4N HCl. The solid obtained was filtered to obtain the crude product. The crude product was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting product was triturated with minimum hexane to obtain the desired product, 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.65 g); Yield: 71.87%; 1H NMR(400 MHz, DMSO-d6): δ 14.79 (s, 1H), 9.08 (s, 1H), 8.45 (d, J=6.4, 1H), 8.22 (d, J=8.8, 1H), 4.60-4.65 (m, 2H), 1.38-1.42 (m, 3H).
- Step 5
- In a 25 mL single neck flask, the intermediate 4 (0.5 g, 1.85 mmol) from Step 4, N-methyl(phenyl)methanamine (1.34 g, 11.11 mmol), CuI (0.04 g, 0.19 mmol) and 1-methylpyrrolidin-2-one (3 mL) were added and the resulting mixture was heated at 150° C. for 12 h and worked up. The reaction mixture was partitioned in dichloromethane/water and the organic layer was separated. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to obtain the pure 7-(N-benzyl-N-methylamino)-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (23 mg); Yield: 5.48%; 1H NMR(400 MHz, CDCl3): δ15.24 (s, 1H), 8.59 (s, 1H), 8.05 (d, J=14, 1H), 7.26-7.38 (m, 5H), 6.61 (d, J=6.8, 1H), 4.64 (s, 2H), 4.16-4.18 (m, 2H), 3.15 (s, 3H), 1.38-1.41 (t, 3H); MS(ESI): 355.0(M+H); HPLC: 96.7%.
-
- In a 25 mL single neck flask, the intermediate 4 (0.55 g, 1.85 mmol) from Example 1, (3-fluorophenyl)-N-methylmethanamine (1.54 g, 11.11 mmol), CuI (0.04 g, 0.19 mmol) and 1-methylpyrrolidin-2-one (3 mL) were added and the resulting mixture was heated at 150° C. for 12 h and worked up. The reaction mixture was partitioned in dichloromethane/water and the organic layer was separated. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to obtain the pure 7-(N-(3-fluorobenzyl)-N-methylamino)-6-fluoro-1, 4-dihydro-1-isobutyl-4-oxoquinoline-3-carboxylic acid (25 mg); Yield: 3.38%; 1H NMR (400 MHz, CDCl3): δ 15.0 (s, 1H), 8.55 (s, 1H), 8.09 (d, J=14, 1H), 7.33-7.37 (m, 1H), 7.07-7.09 (m, 1H), 7.01-7.04 (m, 2H), 6.61 (d, J=7.2, 1H), 4.64 (s, 2H), 3.90-3.92 (m, 2H), 3.18-3.19 (m, 3H), 2.05-2.07 (m, 1H), 0.93-0.94 (m, 6H); MS(ESI): 401.0(M+H); HPLC: 95.2%.
- Example 8
- In a 25 mL single neck flask, the intermediate 4 (0.55 g, 1.85 mmol) from Example 1, (3-methoxyphenyl)-N-methylmethanamine (1.67 g, 11.11 mmol), CuI (0.04 g, 0.19 mmol) and 1-methylpyrrolidin-2-one (3 mL) were added and the resulting mixture was heated at 150° C. for 12 h and worked up. The reaction mixture was partitioned in dichloromethane/water and the organic layer was separated. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to obtain the pure 7-(N-(3-methoxybenzyl)-N-methylamino)-6-fluoro-1,4-dihydro-1-isobutyl-4-oxoquinoline-3-carboxylic acid (25 mg); Yield: 3.29%; 1H NMR (400 MHz, CDCl3): δ 8.52 (s,1H), 8.07 (d, J=14, 6H), 7.28-7.32 (t, 1H), 6.84-6.87 (t, 3H), 6.58 (d, J=7.2, 1H), 4.62 (s, 2H), 3.86 (d, J=7.6, 2H), 3.81(s, 3H), 3.22-3.23 (m, 3H), 1.99-2.06 (m, 1H), 0.89-0.91(m, 6H); MS(ESI): 413.0(M+H); HPLC: 96.5%.
-
- In a 25 mL single neck flask, the intermediate 4 (0.45 g, 1.51 mmol) from Example 1, N-methyl(1-methylpiperidin-4-yl)methanamine (1.29 g, 9.06 mmol), CuI (0.03 g, 0.15 mmol) and 1-methylpyrrolidin-2-one (3 mL) were added and the resulting mixture was heated at 150° C. for 12 h and worked up. The reaction mixture was partitioned in dichloromethane/water and the organic layer was separated. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to obtain the pure 7-(N-methyl-N((1-methylpiperidin-4-yl) methyl) amino)-6-fluoro-1,4-dihydro-1-isobutyl-4-oxoquinoline-3-carboxylic acid (25 mg); Yield: 4.11%; 1H NMR (400 MHz, DMSO-d6): δ 9.02 (br s, 1H), 8.85 (s, 1H), 7.87 (d, J=14.4, 1H), 6.92 (d, J=7.6, 1H), 4.38-4.40 (m, 2H), 3.40-3.42 (m, 4H), 3.12 (s, 3H), 2.88-2.90 (m, 2H), 2.73 (s, 3H), 2.18-2.20 (m, 1H), 1.98 (s, 1H), 1.82-1.85 (m, 2H), 1.41-1.38 (m, 2H), 0.91-0.92 (m, 6H); MS(ESI): 404.0(M+H); HPLC: 99.3%.
-
-
- A mixture of 3-chloro-4-fluoroaniline (20.8 g, 109.5 mmol) and diethyl ethoxymethylenemalonate (23.67 g, 109.5 mmol) was heated at 120-130° C. After 2 h, the resulting EtOH was evaporated off. The crude malonate was used in the successive reaction without further purification. The residue was recrystallized from n-hexane to obtain ethyl diethyl 2-((E)-(3-bromo-4-fluorophenylimino)methyl)malonate (35 g); Yield: 88.76%.
-
- In a 500 mL, 3-neck round-bottomed flask, the intermediate (1) (18 g, 49.975 mmol) and diphenyl ether (180 mL) were added and the resulting mixture was heated at 310° C. for 1 h. After the solution was cooled, the resulting precipitate was filtered off, washed with benzene, and dried. The solid was recrystallized from DMF to obtain the desired product, ethyl 7-bromo-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (9 g); Yield: 57.33%.
-
- In a closed system, ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (2) (5.0 g, 15.918 mmol) and K2CO3 (10.99 g, 79.59 mmol) were suspended in DMF (50 mL) and the reaction mixture was stirred for 15 min at room temperature. To this reaction mixture, 1-bromo-2-methylpropane (13.09 g, 95.508 mmol) and KI (0.26 g, 1.592 mmol) were added, and the reaction mixture was heated at 80° C. for 24 hrs. The reaction mixture was cooled and filtered. The filtrate was partitioned between ethyl acetate and brine solution, and the organic phase was separated, washed with brine solution, and dried over anhydrous Na2SO4 to obtain the crude product which was purified by column chromatography (Silica gel). The fractions containing desired compound were collected together and concentrated under reduced pressure to obtain ethyl 7-bromo-6-fluoro-1,4-dihydro-1-isobutyl-4-oxoquinoline-3-carboxylate (4.9 g); Yield: 83.17%; 1H-NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 8.22 (d, J=8.8, 1H), 7.64 (d, J=5.6, 1H), 4.37-4.43 (m, 2H), 3.93-3.96 (m, 2H), 2.23-2.28 (m, 1H), 1.39-1.43 (m, 3H), 1.00-1.04 (m, 6H).
-
- In a 100 mL, 3-neck round-bottomed flask, the intermediate (3) (0.55 g, 1.486 mmol), N-methyl (thiophen-2-yl)methanamine (1.13 g, 8.916 mmol), (dba)Pd (0.06 g), K2CO3 (0.62 g, 4.458 mmol) and 1,4-dioxane (10mL) were added under N2. The reaction mixture was stirred at 80° C. for 8 h and reaction completion was monitored by TLC. The mixture was added H2O (500 mL) and extracted with EtOAc (500 mL×2). The combined organic layer was washed with brine and dried over anhydrous Na2SO4, concentrated in vacuo to afford a brown solid, which was then purified by silica gel column chromatography to obtain the desired product, ethyl 7-(N-methyl-N-((thiophen-2-yl)methyl)amino)-6-fluoro-1,4-dihydro-1-isobutyl-4-oxoquinoline-3-carboxylate (230 mg); Yield: 37.16%; MS (ESI): 417(M+H).
-
- In a 100 mL, 3-neck round-bottomed flask, the intermediate (5) (0.23 g, 0.552 mmol) was charged with THF: Water (2:1) (10 mL). To this reaction mixture, a 2M NaOH solution (4.4 mL) was added dropwise maintaining the temperature at 0° C. The reaction mixture was stirred at 80° C. for 2 h and the reaction completion was monitored by TLC. The mixture was cooled to 0° C. and acidified to pH 3-4 by 4N HCl. The solid obtained was filtered to obtain the crude product which was purified by silica gel column chromatography to provide 7-(N-methyl-N-((thiophen-2-yl) methyl) amino)-6-fluoro-1, 4-dihydro-1-isobutyl-4-oxoquinoline-3-carboxylic acid (25 mg); Yield: 8.25%; 1-HNNIR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.21 (d, J=6.4, 1H), 8.14-8.17 (m, 2H), 7.84 (d, J=3.6, 2H), 7.21 (d, J=3.2, 1H), 4.55-4.56 (m, 2H), 4.02 (s, 2H), 2.39 (s, 3H), 2.12-2.18 (m, 1H), 0.94 (m, 6H); MS(ESI): 389.0(M+H); HPLC: 96.9%.
-
-
- In a 25 mL single neck flask, the intermediate 4 (1.36 g, 4.568 mmol) from Example 1, methanamine (0.85 g, 27.41 mmol), CuI (0.087 g, 0.46 mmol) and 1-methylpyrrolidin-2-one (5 mL) were added and the resulting mixture was heated at 150° C. for 12 h and worked up. The reaction mixture was partitioned in dichloromethane/water and the organic layer was separated. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to obtain the pure 6-fluoro-1,4-dihydro-1-isobutyl-7-(methylamino)-4-oxoquinoline-3-carboxylic acid (70 mg); Yield: 5.25%; 1H NMR (400 MHz, CDCl3): δ 15.39 (s, 1H), 8.55 (s, 1H), 8.02 (d, J=11.6, 1H), 6.42-5.43 (t, 1H), 4.88-4.90 (t, 1H), 4.01-4.03 (m, 2H), 3.03-3.04 (m, 3H), 2.30-2.35 (m, 1H), 1.00-1.04 (m, 6H).
-
- In a 25 mL single neck flask, the intermediate 5 (93 mg, 0.32 mmol), benzoyl chloride (1.67 g, 11.11 mmol), toluene (10 mL) were added and the resulting mixture was heated at 120° C. for 12 h and worked up. The reaction mixture was partitioned in dichloromethane/water and the organic layer was separated. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to obtain the pure 7-(N-methylbenzamido)-6-fluoro-1,4-dihydro-1-isobutyl-4-oxoquinoline-3-carboxylic acid (25 mg); Yield: 19.73%; 1H NMR (400 MHz, DMSO-d6): δ 15.0 (s, 1H), 8.66 (s, 1H), 8.26 (d, J=8.0, 2H), 7.32 (s, 3H), 7.24-7.27 (m, 2H), 7.13 (s, 1H), 3.86 (s, 2H), 3.55 (s, 3H), 1.26 (s, 1H), 0.75-0.76 (m, 6H); MS(ESI): 397.0(M+H); HPLC: 95.2%.
-
-
- In a closed system, ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (2) (1.5 g, 5.562 mmol) and K2CO3 (3.843 g, 27.809 mmol) were suspended in DMF (15 mL) and the reaction mixture was stirred for 15 min at room temperature. To this reaction mixture, 1-(bromomethyl) benzene (5.707 g, 33.37 mmol) and KI (0.092 g, 0.556 mmol) were added, and the reaction mixture was heated at 80° C. for 24 h. The reaction mixture was then cooled and filtered. The filtrate was partitioned between ethyl acetate and brine solution, and the organic phase was separated, washed with brine solution, and solvent was removed under reduced pressure to obtain the crude product which was purified by column chromatography (Silica gel).. The fractions containing desired compound were collected together and concentrated in vacuo to obtain ethyl 1-benzyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.1 g); Yield: 54.94%.
-
- In a 100 mL, 3-neck round-bottomed flask, the intermediate (3) (1.1 g, 3.06 mmol) was charged with THF: Water (2:1) (8 mL). To this reaction mixture, a 2M NaOH solution (6.12 mL) was added dropwise maintaining the temperature at 0° C. The reaction mixture was stirred at 80° C. for 2 h, cooled to 0° C. and acidified to pH 3-4 by 4N HCl. The solid obtained was filtered to obtain the crude product, 1-benzyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.9 g); Yield: 88.86%; 1H NMR (400 MHz, DMSO_d6): δ 14.68 (s, 1H), 9.27 (d, J=3.2, 1H), 8.21-8.24 (t, 1H), 7.27-7.40 (m, 5H), 5.88-5.90 (m, 2H).
-
- In a 25 mL single neck flask, the intermediate 4 (0.4 g, 1.21 mmol), (3-methoxyphenyl)-N-methylmethanamine (1.09 g, 7.23 mmol), CuI (0.023 g, 0.12 mmol) and 1-methylpyrrolidin-2-one (3 mL) were added and the resulting mixture was heated at 150° C. for 12 h and worked up. The reaction mixture was partitioned in dichloromethane/water and the organic layer was separated. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to obtain the pure 7-(N-(3-methoxybenzyl)-N-methylamino)-1-benzyl-6-fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (25 mg); Yield: 4.63%; 1H NMR (400 MHz, CDCl3): δ 15.0 (s, 1H), 8.77 (s, 1H), 8.01 (d, J=14, 1H), 7.33 (s, 3H), 7.22-7.26 (t, 1H), 7.04 (d, J=18.4, 2H), 6.82 (d, J=7.2, 1H), 6.70-6.74 (m, 2H), 6.52 (d, J=5.6, 1H), 5.30 (s, 2H), 4.43 (s, 2H), 3.71-7.76 (m, 3H), 2.92(s, 3H); MS(ESI): 447.0(M+H); HPLC: 98.0%.
-
- In a 25 mL single neck flask, the intermediate 4 (0.45 g, 1.51 mmol) from Example 1, (tetrahydro-2H-pyran-4-yl)-N-methylmethanamine (1.17 g, 9.06 mmol), CuI (0.03 g, 0.15 mmol) and 1-methylpyrrolidin-2-one (3 mL) were added and the resulting mixture was heated at 150° C. for 12 h and worked up. The reaction mixture was partitioned in dichloromethane/water, and the organic layer was separated. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to obtain the pure 7-(N-((tetrahydro-2H-pyran-4-yl) methyl)-N-methylamino)-6-fluoro-1,4-dihydro-1-isobutyl-4-oxoquinoline-3-carboxylic acid (28 mg); Yield: 4.74%; 1H NMR (400 MHz, CDCl3): δ 15.0 (s, 1H), 8.54 (s, 1H), 7.01 (d, J=14.4, 1H), 6.59 (d, J=7.2, 1H), 3.97-4.01 (m, 4H), 3.34-3.41 (m, 4H), 3.13 (s, 3H), 2.27-2.30 (m, 1H), 2.01 (s, 1H), 1.59-1.62 (m, 2H), 1.35-1.43 (m, 2H), 1.03-1.04 (m, 6H); MS(ESI): 391.0(M+H); HPLC: 98.8%.
-
-
- In a 250 mL, 3-neck round-bottomed flask, 2-methyl-4-nitrobenzoic acid (20 g, 93.8 mmol) was charged with methanol (100 mL) and sulfuric acid (4 mL). The reaction mixture was refluxed for 15 h. After completion, the reaction mixture was concentrated to obtain the crude product which was added water (200 mL) and basified to pH 7-8 with aqueous NaHCO3 solution. Aqueous solution was extracted with dichloromethane (250 mL×3), the organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate. The solvent was removed to obtain methyl 2-methyl-4-nitrobenzoate (1), 20 g; Yield: 94.65%.
-
- In a 500 mL, 3-neck round-bottomed flask, the intermediate (1) (20 g, 88.01 mmol) was charged with CCl4 (100 mL). N-bromosuccinimide (39.16g, 220.03 mmol) and AIBN (2.16 g, 13.20 mmol) were added and the resulting mixture was refluxed for 20 h. The reaction mixture was quenched with water (500 mL), extracted with dichloromethane (200 mL×3), and the combined organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate. The organic layer was evaporated under reduced pressure and the crude product obtained was purified by silica gel column chromatography to obtain pure methyl 2-(bromomethyl)-4-nitrobenzoate (2), 19 g; Yield: 78.7%; 1H NMR (400 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.27-8.3(dd, 1H), 8.07-8.1(d, 1H), 5.1 (s, 2H), 3.94 (s, 1H).
-
- In a 100 mL, 3-neck round-bottomed flask, 2,5-dimethyl-1H-pyrazole (5.26 g, 54.73 mmol) and K2CO3 (7.97 g, 54.73 mmol) were suspended in DMF (100 mL) and the reaction mixture was stirred for 15 min at room temperature. To this reaction mixture, the intermediate (2) (10 g, 36.48 mmol) was added and the resulting mixture was stirred at 60° C. for 6 h. The reaction mixture was cooled, filtered and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain methyl 2-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-4-nitrobenzoate(3), 6 g; Yield: 56.78%; MS(ESI): 290.4(M+H).
-
- The intermediate (3) (10 g, 20.74 mmol), palladium on carbon (5%) (1.2 g) and methanol (60 mL) were charged in a hydrogenator. The reaction mixture was stirred at 10 bar pressure of hydrogen pressure at room temperature for 6 h. After completion, reaction mixture was filtered through celite bed and filtrate was evaporated under reduced pressure. The crude product obtained was purified by triturating with hexanes to obtain methyl 4-amino-2-((3, 5-dimethyl-1H-pyrazol-1-yl) methyl)benzoate (4), 5 g; Yield: 93.17%; MS(ESI): 260.3(M+1).
-
- In a 250 mL, 3-neck round-bottomed flask, the intermediate (4) (5 g, 19.28 mmol) was charged with toluene (100 mL) and diethyl-2-(ethoxymethylene) malonate (4.16 g, 19.28 mmol) was added at 25° C. The reaction mixture was refluxed for 1 h. The reaction mixture was then cooled to room temperature and hexane was added to precipitate the compound. The solid thus obtained was filtered to obtain diethyl-2-((3-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-4-(methoxycarbonyl)phenylamino) methylene)malonate (5), 5 g; Yield: 60.97%; MS(ESI): 430.1(M+1).
-
- In a 100 mL, 3-neck round-bottomed flask, diphenylether (200 mL) was heated upto 150° C. The intermediate (5) (5 g, 11.87 mmol) was added to the reaction mixture and stirred at that temperature for 4 h. The reaction mixture was then cooled to room temperature, and hexanes (300 mL) was added to precipitate the compound. The solid obtain was filtered to obtain 0.7 g of 3-ethyl 6-methyl 7-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-4-oxo-1,4-dihydroquinoline-3,6-dicarboxylate(6); Yield: 15.69%. The crude product contained traces of regioisomer formed during cyclization. This product was used for the next step without further purification.
-
- In a 100 mL, 3-neck round-bottomed flask, the intermediate (6) (0.7 g, 1.82 mmol) and K2CO3 (1.2 g, 9.1 mmol) were suspended in DMF (10 mL), and the reaction mixture was stirred for 15 min at room temperature. To this reaction mixture, were added 1-bromo-2-methyl propane (1.5 g, 10.95 mmol) and KI (0.030 g, 0.18 mmol) and the resulting mixture was heated at 80° C. for 6 h. The reaction mixture was cooled and quenched with water, and was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain the crude compound which was purified by silica gel column chromatography to provide 3 -ethyl-6-methyl 7-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1-isobutyl-4-oxo-1,4-dihydro-quinoline-3,6-dicarboxylate (7), 0.34 g; Yield: 42.5%; MS(ESI): 440.2(M+1). Step 8
- In a 25 mL single neck round bottom flask, the intermediate (7) (0.3 g, 0.682 mmol) was charged with THF/Water(1:1) (5 mL) at 0° C. and LiOH (0.028 g, 0.681 mmol) was added to the the mixture. The resulting mixture was stirred at 0° C. for 30-50 min. The reaction was closely monitored for selective mono hydrolysis by mass spectroscopy and TLC. After completion, the mixture was acidified to pH 2 by 4 N HCl and the product was extracted with dichloromethane (50 mL×3). The combined organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate to obtain the crude product. The crude product was purified by silica gel column chromatographyto obtain 7-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-3-(ethoxycarbonyl)-1-isobutyl-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (8), 0.2 g; Yield: 69.96%; MS(ESI): 425.8(M+H), 440.2(M+15).
-
- In a 25 mL single neck round-bottomed flask, the intermediate (8) (0.2 g, 0.47 mmol) was charged with DMF (2 mL). To this reaction mixture, were added azetidine HCl (0.043 g, 0.47 mmol), EDC.HCl (0.094 g, 0.611 mmol) and DMAP (5 mg, 0.047 mmol) and the resulting mixture was stirred for 2 h at room temperature. After completion, the reaction was quenched with water and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain the crude product which was purified by silica gel column chromatography to provide ethyl 6-(azetidine-1-carbonyl)-7-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (9), 0.14 g; Yield: 58.33%; MS(ESI): 465.1(M+H).
-
- In a 100 mL, 3-neck round-bottomed flask, the intermediate (9) (0.14 g) was added with THF: Water (1:1) (3 mL). To this reaction mixture, was added 2M KOH solution (1 mL) dropwise at 0° C. and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and acidified to pH 3-4 with 4 N HCl. The crude product was extracted with EtOAc (30 mL×3) and the combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 6-(azetidine-1-carbonyl)-7-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (10), 40 mg; Yield: 30.7%.; 1H NMR (400 MHz, DMSO-d6): δ 14.92 (s, 1H), 7.27-8.21 (m, 3H), 5.91 (s, 1H), 5.44 (s, 2H), 3.83-4.2 (m, 2H×3), 2.1-2.2 (m, 3H×2), 2.2 (m, 2H), 0.83-0.85 (d, 6H); MS(ESI): 437.3(M+H); HPLC: 97.24%.
-
-
- In a closed system, ethyl-7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (2) (2 g, 0.743 mmol) and K2CO3 (0.51 g, 3.715 mmol) were suspended in DMF (20 mL) and the reaction mixture was stirred for 15 min at room temperature. To this reaction mixture, isopropyl bromide (0.54 g, 4.46 mmol) and KI (0.012 g, 0.074 mmol) were added and the mixture was heated at 80° C. for 24 h. The reaction mixture was cooled and filtered. The obtained filtrate was partitioned between EtOAc and brine solution, and the organic phase was separated and washed with brine solution to obtain crude ethyl-7-chloro-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate. The crude product was purified by column chromatography (Silica gel) and the solvent was removed in vacuo to obtain ethyl 7-chloro-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (3), 0.5g; Yield: 21.74%.
-
- In 100 mL, 3-neck round-bottomed flask, the intermediate (3) (0.4 g, 1.28 mmol) was charged with THF: Water (1:1) (5 mL). To this reaction mixture, 2 M KOH solutions (5 mL) was added dropwise maintaining temperature at 0° C. The resulting mixture was stirred at room temperature for 2 h, cooled to 0° C. and acidified to pH 3-4 by aqueous 4N HCl. The solid obtained was filtered to obtain the crude 7-chloro-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid which was extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated in vacuo, triturated with minimum hexane to obtain 7-chloro-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.3 g); Yield: 83.33%.
-
- In 25 mL single neck flask, the intermediate (4) (0.2 g, 0.70 mmol) and N-methyl-1-(pyridin-3-yl)methanamine (0.43 g, 3.42 mmol) were added, and the reaction mixture was heated at 120° C. for 24 h and worked up. The reaction mixture was partitioned in dichloromethane/water and the organic layer was separated. The organic layer was washed with 30% HCl solution, dried over anhydrous Na2SO4, and the solvent was removed in vacuo to obtain the crude product. The crude product was treated with EtOAc: hexane (50:50) (10 Vol) and heated at 60° C. for 15 min. Then the reaction was brought to room temperature, and the solid was filtered. The filtrate was concentrated to obtain crude solid which was triturated with ether to obtain the pure 6-fluoro-1-isopropyl-7-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (30 mg); Yield: 11.5%; 1H NMR (400 MHz, DMSO-d6): δ 15.45 (s, 1H), 8.73 (s,1H), 7.14-8.55 (m, 6H), 5.18-5.22 (m, 1H), 4.72 (s, 2H), 3.12 (s, 3H), 1.48-1.56 (d, J=6.4, 6H); MS(ESI): 370(M+H); HPLC: 96.4%.
-
- In 25 mL single neck flask, the intermediate (4) (1.4 g, 4.94 mmol) from Example 16 and N-benzyl methylamine (2.9 g, 24.7 mmol) were added, and the reaction mixture was heated at 120° C. for 24 h and worked up. The reaction mixture was partitioned in dichloromethane/water and the organic layer was separated. The organic layer was washed with aqueous 4N HCl solution, dried over anhydrous Na2SO4, and the solvent was removed in vacuo to obtain the crude product. The crude product was treated with EtOAc: hexane (50:50) (10 Vol) and heated at 60° C. for 15 min. Then the reaction was brought to room temperature, and the solid was filtered. The filtrate was concentrated to obtain crude solid which was triturated with ether to obtain the pure 6-fluoro-1-isopropyl-7-(methyl(pyridin-3-ylmethyl)amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (20 mg); Yield: 1.1%; 1H NMR (400 MHz, DMSO-d6): δ 15.50 (s, 1H), 8.72 (s,1H), 7.10-7.93 (m, 6H), 5.16 (m, 1H), 4.69 (s, 2H), 3.12 (s, 3H), 1.46-1.48 (d, 6H); MS(ESI): 368.6(M+H); HPLC: 94.64%.
-
- In 25 mL single neck flask the intermediate 4 (1.4 g, 4.94 mmol) from Example 16 and 1-(4-fluorophenyl)-N-methylmethanamine (3.4 g, 24.73 mmol) were added and heated at 120° C. for 24 h and worked up. The reaction mixture was partitioned in dichloromethane/water mixture and the organic layer was separated. The organic phase was washed with aqueous 4N HCl, dried over anhydrous Na2SO4, and the solvent was evapremoved in vacuo to obtain the crude product. The crude product was washed with hot EtOAc: Hexane (50:50) (10 Vol) and heated at 60° C. for 15 min. The solid obtained was washed with ether to obtain 0.2 g of pure 6-fluoro-7-((4-fluorobenzyl)(methyl)amino)-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid); Yield: 10.52%; 1-EINMR (400 MHz, DMSO-d6): δ 15.47 (s, 1H), 8.72 (s,1H), 7.93-7.10 (m, 6H), 5.19 (m, 1H), 4.66 (s, 2H), 3.10 (s, 3H), 1.49-1.47 (d, 6H), MS(ESI): 386.9(M+H); HPLC:98.48%.
-
TABLE 1 Lactate Inhibition Example Structure Name Cytotoxicity [EC50] 1 7-(benzyl(methyl)amino)-6- fluoro-1-isobutyl-4-oxo-1,4- dihydroquinoline-3- carboxylic acid A 2 6-(benzyl(methyl)amino)-7- chloro-1-isobutyl-4-oxo-1,4- dihydroquinoline-3- carboxylic acid C 3 6-fluoro-1-isobutyl-7- (methyl(3-(trifluoro- methyl)benzyl)amino)- 4-oxo-1,4- dihydroquinoline-3- carboxylic acid A 4 7-((4-chlorobenzyl) (methyl)amino)-6- fluoro-1-isobutyl-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid A 5 6-fluoro-1-isobutyl-4- oxo-7-((3-(trifluoro- methyl)benzyl)amino)- 1,4-dihydroquinoline- 3-carboxylic acid A 6 7-(benzyl(methyl)amino)- 1-ethyl-6-fluoro-4-oxo- 1,4-dihydroquinoline-3- carboxylic acid A 7 6-fluoro-7-((3- fluorobenzyl)(methyl) amino)-1-isobutyl-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid A 8 6-fluoro-1-isobutyl-7- ((3-methoxybenzyl) (methyl)amino)-4-oxo- 1,4-dihydroquinoline- 3-carboxylic acid A 9 6-fluoro-1-isobutyl-7- (methyl((1-methyl- piperidin-4-yl)methyl) amino)-4-oxo-1,4- dihydroquinoline-3- carboxylic acid A 10 6-fluoro-1-isobutyl-7- (methyl(thiophen-2- ylmethyl)amino)-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid A 11 6-fluoro-1-isobutyl-7- (N-methylbenzamido)- 4-oxo-1,4-dihydro- quinoline-3-carboxylic acid A 12 1-benzy1-6-fluoro-7- ((3-methoxybenzyl) (methyl)amino)-4-oxo- 1,4-dihydroquinoline- 3-carboxylic acid A 13 6-fluoro-1-isobutyl-7- (methyl((tetrahydro- 2H-pyran-4-yl)methyl) amino)~4-oxo-1,4- dihydroquinoline-3- carboxylic acid NT 15 6-(azetidine-1-carbonyl)- 7-((3,5-dimethyl-1H- pyrazol-1-yl)methyl)-1- isobutyl-4-oxo-1,4- dihydroquinoline-3- carboxylic acid A 16 6-fluoro-1-isopropyl-7- (methyl(pyridin-3- ylmethyl)amino)-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid A 17 7-(benzyl(methyl)amino)- 6-fluoro-1-isopropyl-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid A 18 6-fluoro-7-((4- fluorobenzyl)(methyl) amino)-1-isopropyl-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid A 19 bis(trifluoromethyl) benzyl)(methyl)amino)- 6-fluoro-1-isobutyl-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid NT 20 7-((cyclohexylmethyl) (methyl)amino)-6- fluoro-1-isobutyl-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid NT 21 6-fluoro-1-isobutyl-7- (methyl(thiazol-5- ylmethyl)amino)-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid NT 22 6-fluoro-1-isobutyl-7- (methyl(oxazol-5- ylmethyl)amino)-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid NT 23 1-benzyl-6-fluoro-7- (N-methylbenzamido)- 4-oxo-1,4-dihydro- quinoline-3-carboxylic acid NT 24 6-fluoro-7-(N-methyl- benzamido)-4-oxo-1- (pyridin-3-ylmethyl)- 1,4-dihydroquinoline- 3-carboxylic acid NT 25 6-(azetidine-1-carbonyl)- 7-(benzyl(methyl) amino)-1-isobutyl-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid NT 26 7-(benzyl(methyl) amino)-1-isobutyl- 4-oxo-1,4-dihydro- quinoline-3-carboxylic acid NT 27 6-(azetidine-1- carbonyl)-7-((3,5- dimethyl-1H-pyrazol- 4-yl)methyl)-1- isobutyl-4-oxo-1,4- dihydroquinoline- 3-carboxylic acid NT 28 7-((3,5-dimethyl-1H- pyrazol-4-yl)methyl)- 6-fluoro-1-isobutyl-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid NT 29 7-((3,5-dimethyl-1H- pyrazol-4-yl)methyl)- 6-fluoro-1-isopropyl- 4-oxo-1,4-dihydro- quinoline-3-carboxylic acid NT 30 6-cyano-7-((3,5- dimethyl-1H-pyrazol- 4-yl)methyl)-1- isopropyl-4-oxo-1,4- dihydroquinoline-3- carboxylic acid NT 31 7-((3,5-dimethyl-1H- pyrazol-4-yl)methyl)- 1-isopropyl-4-oxo-6- (trifluoromethyl)-1,4- dihydroquinoline-3- carboxylic acid NT 32 7-(benzyl(methyl)amino)- 6-fluoro-1-isopropyl-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid NT 33 7-(benzyl(methyl)amino)- 6-cyano-1-isopropyl-4- oxo-1,4-dihydro- quinoline-3-carboxylic acid NT 34 7-(benzyl(methyl)amino)- 1-isopropyl-4-oxo-6- (trifluoromethyl)-1,4- dihydroquinoline-3- carboxylic acid NT 35 7-((4-chlorobenzyl) (methyl)amino)-6- fluoro-1-isopropyl- 4-oxo-1,4- dihydroquinoline-3- carboxylic acid NT 36 6-(benzyl(methyl) amino)-7-fluoro-1- isobutyl-4-oxo-1,4- dihydroquinoline-3- carboxylic acid NT 37 6-fluoro-1-isopropyl- 4-oxo-7-(2- (trifluoromethyl) benzyl)-1,4-dihydro- quinoline-3-carboxylic acid NT 38 6-fluoro-1-isobutyl- 4-oxo-7-(2- (trifluoromethyl) benzyl)-1,4-dihydro- quinoline-3-carboxylic acid NT 39 7-(benzyl(methyl) amino)-6-fluoro-1- isopropyl-4-oxo-1,4- dihydro-1,8-naph- thyridine-3-carboxylic acid NT 40 6-(benzyl(methyl) amino)-7-chloro-1- isopropyl-4-oxo-1,4- dihydro-1,8-naph- thyridine-3-carboxylic acid NT 41 3-(benzyl(methyl) amino)-2-fluoro-5- isopropyl-8-oxo-5,8- dihydropyrido[2,3-b] pyrazine-7-carboxylic acid NT 42 2-(benzyl(methyl) amino)-3-chloro-5- isopropyl-8-oxo-5,8- dihydropyrido[2,3-b] pyrazine-7-carboxylic acid NT 43 7-(benzyl(methyl) amino)-6-fluoro-1- isopropyl-4-oxo-1,4- dihydro-1,5-naph- thyridine-3-carboxylic acid NT 44 6-(benzyl(methyl) amino)-7-chloro-1- isopropyl-4-oxo-1,4- dihydro-1,5-naph- thyridine-3-carboxylic acid NT A = <1 uM; B = 1-10 uM; C = >10 uM; NT = Not Tested - MTS or MTT Cell Proliferation Assay
- Cytotoxicity of the inhibition of monocarboxylate transporters of the invention was determined and are shown in Table 1. The anti-proliferation effect of MCT inhibition was investigated across a panel of solid and haemotological tumor cell lines. Cells were routinely cultured in their appropriate growth medium. On day 1, between 5,000 -10,000 cells/well were plated into 96-well plates. 100 μL of phosphate buffered saline solution was added to the external wells to prevent media evaporation. Plates were incubated overnight at 37° C. in the presence of 5% CO2. On day 2, dry weight compound stocks were dissolved to a concentration of 20 mM in 100% DMSO. Compounds were further diluted in either growth medium or 10 mM lactate medium (For SiHa cell lines; Basic DMEM, 10% FBS, 10 mM Na-Lactate, 2.2 g/L NaHCO3, no glutamine) to generate a final dose range of 10 nM to 100 μM. Plates were then incubated at at 37° C. in the presence of 5% CO2 for a further 72 hours post-dosing. On day 5, 20 μL of CellTiter 96 AQ MTS reagent or MTT was added to each well and the plate was returned to the incubator for 2-4 hours. In case of lactate medium, the medium was replaced by 100 μL of growth medium and 20 μL of CellTiter 96 AQ MTS reagent or replaced the media in cells with 100 uL of growth media containing 10% MTT solution,. MTS or MTT is bioreduced by NADPH or NADH produced by dehydrogenase enzymes in metabolically active cells into a coloured formazan product that is soluble in tissue culture medium. The amount of coloured formazan product is directly proportional to the number of living cells in culture. In the case of MTT, after 4 hr incubation, the media was removed from the plates and the plate was air-dried. Then, 100 uL of DMSO was added to each well, and incubated for 30 mins at room temperature with mild shaking. The absorbance of the plates was read on a Synergy H4 plate reader using 490 nM or 540 nm measurement wavelength. Dose response curves were plotted and IC50 values were calculated using Prism. The IC50 value is equivalent to the concentration of compound that causes 50% inhibition of growth calculated from the compound treated signal to the vehicle treated signal.
- Lactate Consumption Assay in Tumor Cell Lines.
- The inhibition of monocarboxylate transporters of the invention was determined and data are shown in Table II. Cells are maintained in their appropriate growth medium (DMEM medium with 4.5 g/L glucose, 4 mM L-glutamine supplemented with 10% FBS and P/S (growth medium). Cells (500,000 cells/well) were seeded in 24-well plate in growth medium for 6 hours. Replace the growth medium with 1 mL lactate medium (10 mM lactate in base DMEM without sodium pyruvate) for overnight. Cells were treated with compounds in 1 mL lactate medium for 24 hours. The culture medium was collected and centrifuged at 12,000 rpm for 5 minutes at 4° C. to get rid of any cell debris. An aliquot of 0.5 mL of the supernatant was loaded to a deproteinizing column, centrifuged at 12,000 rpm for 15 minutes at 4° C. The flow-through was collected and stored at -80° C. for future analysis. The amount of lactate in the supernatant was analyzed by enzymatic L-Lactate Kit II (Eton Bioscience Inc.). Briefly, 50 μL of 10 times diluted sample was mixed with 50 μL reaction mixture. Lactic acid is oxidized by enzyme reactions to yield color product, which can be measured in dual modes, either at 570 nm for colorimetric assay or with Ex 530-560/Em 570-595 nm fluorescence assay. And the color or fluorescence intensity is proportional to lactic acid concentrations, therefore the sample lactic acid concentration can be accurately calculated based on the lactic acid standards. The signal was read on a Synergy H4 plate reader using 570 nM measurement wavelength, and the lactate consumption was calculated by medium lactate concentration at start point (10 mM) subtracted the end point.
- Measuring Lactate Uptake by 14 C-lactate Labeling Assay.
- The inhibition of monocarboxylate transporters of the invention was determined using 14CLactate, and the data are shown in Table II. Cells are maintained in their appropriate growth medium (DMEM medium with 4.5 g/L glucose, 4 mM L-glutamine supplemented with 10% FBS and P/S (growth medium). Cell culture surface of 24-well cell culture plates (BD Bioscience) were aseptically coated with 80 μL poly-lysine (1 mg/mL, Sigma) for 5 mins, then rinsed with sterile cell culture grade water, air-dried for at least 2 hours before introducing cells and medium. SiHa cells were seeded in poly-lysine coated 24-well plate at 500,000 cells/well in growth medium for 6 hours. Replace the growth medium with 1 mL lactate medium (10 mM lactate in base DMEM without sodium pyruvate) for overnight. Cells were rinsed with modified Kreb solution (containing 10 μM L-lactate, without glucose) and then treated with vehicle or increasing concentrations of compounds (0.1, 1, 10, 100 μM) at 37° C. in 1 mL modified Kreb solution (containing 10 μM L-lactate, 0.25% BSA) for one hour. Cells were labeled with 2 μM 14C-lacate in modified Kreb solution for 12 minutes, rinsed with ice-cold D-lactate containing Kreb solution (10 μM D-lactate, without glucose), and lysed with 0.1 M NaOH. An aliquot of sample was taken to measure protein concentration by Bradford reagent, and the rest of sample was incubated with liquid scintillation solution. After one hour agitation, the radioactivity was measured using Microbeta TriLux. CPM value was recorded and normalized to protein concentration.
Claims (19)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/527,137 US10766863B2 (en) | 2014-11-17 | 2015-11-17 | Monocarboxylate transport modulators and uses thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462080703P | 2014-11-17 | 2014-11-17 | |
PCT/US2015/061101 WO2016081464A1 (en) | 2014-11-17 | 2015-11-17 | Monocarboxylate transport modulators and uses thereof |
US15/527,137 US10766863B2 (en) | 2014-11-17 | 2015-11-17 | Monocarboxylate transport modulators and uses thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
US20180290978A1 true US20180290978A1 (en) | 2018-10-11 |
US10766863B2 US10766863B2 (en) | 2020-09-08 |
Family
ID=56014456
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/527,137 Active US10766863B2 (en) | 2014-11-17 | 2015-11-17 | Monocarboxylate transport modulators and uses thereof |
Country Status (5)
Country | Link |
---|---|
US (1) | US10766863B2 (en) |
EP (1) | EP3221295B1 (en) |
JP (1) | JP2017538689A (en) |
CN (1) | CN107406390B (en) |
WO (1) | WO2016081464A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021061929A1 (en) * | 2019-09-25 | 2021-04-01 | Nirogy Therapeutics, Inc. | Bicyclic carboxylates as modulators of transporters and uses thereof |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10519154B2 (en) | 2016-07-11 | 2019-12-31 | Bayer Pharma Aktiengesellschaft | 7-substituted 1-pyridyl-naphthyridine-3-carboxylic acid amides and use thereof |
JOP20190045A1 (en) | 2016-09-14 | 2019-03-14 | Bayer Ag | 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof |
EP3296298A1 (en) | 2016-09-14 | 2018-03-21 | Bayer Pharma Aktiengesellschaft | 7-substituted 1-aryl-naphthyridin-3-carboxamides and their use |
CN106892869A (en) * | 2017-03-21 | 2017-06-27 | 厦门法茉维特动物药业有限公司 | A kind of method for preparing Abbott 56619 |
CN108484577B (en) * | 2018-03-05 | 2021-03-30 | 复旦大学 | Pyrimidine-quinolone heterozygote and preparation method and application thereof |
AU2019317518B2 (en) * | 2018-04-25 | 2023-05-25 | Charles R. Drew University Of Medicine And Science | Novel MCT4 inhibitors and uses thereof |
CN111533729B (en) * | 2020-05-07 | 2022-07-26 | 盐城工学院 | Tetrazole-substituted quinolinone derivative and preparation method and application thereof |
EP4340843A1 (en) | 2021-05-21 | 2024-03-27 | CeMM - Forschungszentrum für Molekulare Medizin GmbH | 1,2,4-triazolo[1,5-a]pyrimidine-based slc16a3 inhibitors and their therapeutic use |
WO2022243574A1 (en) | 2021-05-21 | 2022-11-24 | Cemm - Forschungszentrum Für Molekulare Medizin Gmbh | 3-(phthalazin-1-yl)benzenesulfonamide-based slc16a3 inhibitors and their therapeutic use |
CN113845476B (en) * | 2021-11-08 | 2024-04-30 | 中国药科大学 | Quinolone derivative and preparation method and application thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1070333A (en) * | 1964-04-24 | 1967-06-01 | Lilly Industries Ltd | New quinolone derivatives and compositions comprising them |
US3472859A (en) * | 1966-11-01 | 1969-10-14 | Sterling Drug Inc | 1-alkyl-1,4-dihydro-4-oxo-3 quinoline-carboxylic acids and esters |
US7402674B2 (en) * | 2004-01-31 | 2008-07-22 | Sanofi-Aventis Deutschland Gmbh, | 7-Phenylamino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments |
US20120093917A1 (en) * | 2009-04-02 | 2012-04-19 | Robert Hromas | Metnase and intnase inhibitors and their use in treating cancer |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8429142D0 (en) * | 1984-11-19 | 1984-12-27 | Fujisawa Pharmaceutical Co | Quinolone compounds |
SE9904108D0 (en) | 1999-11-15 | 1999-11-15 | New Pharma Research Ab | New compounds |
CZ2004764A3 (en) * | 2002-11-20 | 2005-02-16 | Japan Tobacco Inc | 4-Oxoquinoline compound and use thereof as HIV-integrase inhibitor |
CN100375742C (en) * | 2002-11-20 | 2008-03-19 | 日本烟草产业株式会社 | 4-oxoquinoline compounds and utilization thereof as HIV integrase inhibitors |
EP1650192A4 (en) * | 2003-07-24 | 2007-03-21 | Astellas Pharma Inc | Quinolone derivative or salt thereof |
DE102004004973A1 (en) * | 2004-01-31 | 2005-09-01 | Aventis Pharma Deutschland Gmbh | New 7-phenylamino-quinolone or 1,8-naphthyridone derivatives, useful e.g. for treating type II diabetes or arteriosclerosis, are inhibitors of glycogen phosphorylase |
JP2010037198A (en) * | 2006-11-22 | 2010-02-18 | Astellas Pharma Inc | Quinolone derivative or its pharmaceutically acceptable salt |
RU2543714C2 (en) * | 2009-03-20 | 2015-03-10 | Вертекс Фармасьютикалз Инкорпорейтед | Method of obtaining modulators of cystic fibrousis transmembrane conductance regulator |
-
2015
- 2015-11-17 JP JP2017527664A patent/JP2017538689A/en active Pending
- 2015-11-17 WO PCT/US2015/061101 patent/WO2016081464A1/en active Application Filing
- 2015-11-17 US US15/527,137 patent/US10766863B2/en active Active
- 2015-11-17 CN CN201580073081.0A patent/CN107406390B/en active Active
- 2015-11-17 EP EP15861509.6A patent/EP3221295B1/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1070333A (en) * | 1964-04-24 | 1967-06-01 | Lilly Industries Ltd | New quinolone derivatives and compositions comprising them |
US3472859A (en) * | 1966-11-01 | 1969-10-14 | Sterling Drug Inc | 1-alkyl-1,4-dihydro-4-oxo-3 quinoline-carboxylic acids and esters |
US7402674B2 (en) * | 2004-01-31 | 2008-07-22 | Sanofi-Aventis Deutschland Gmbh, | 7-Phenylamino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments |
US20120093917A1 (en) * | 2009-04-02 | 2012-04-19 | Robert Hromas | Metnase and intnase inhibitors and their use in treating cancer |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021061929A1 (en) * | 2019-09-25 | 2021-04-01 | Nirogy Therapeutics, Inc. | Bicyclic carboxylates as modulators of transporters and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
WO2016081464A1 (en) | 2016-05-26 |
CN107406390B (en) | 2021-04-16 |
JP2017538689A (en) | 2017-12-28 |
CN107406390A (en) | 2017-11-28 |
EP3221295A1 (en) | 2017-09-27 |
US10766863B2 (en) | 2020-09-08 |
EP3221295B1 (en) | 2021-04-14 |
EP3221295A4 (en) | 2018-06-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10766863B2 (en) | Monocarboxylate transport modulators and uses thereof | |
JP6768857B2 (en) | Lysine-specific inhibitor of demethylase-1 | |
US10124004B2 (en) | Pyrido[3,4-d]pyrimidine derivative and pharmaceutically acceptable salt thereof | |
US9937155B2 (en) | Methods of use for trisubstituted benzotriazole derivatives as dihydroorotate oxygenase inhibitors | |
US10662187B2 (en) | Bruton's tyrosine kinase inhibitors | |
US8309721B2 (en) | HSP90 inhibitory carbazole derivatives, compositions containing same and use thereof | |
JP2016523922A (en) | Tricyclic pyrido-carboxamide derivatives as ROCK inhibitors | |
US20130225581A1 (en) | Nitrogen-containing aromatic heterocyclic derivative | |
US11028054B2 (en) | 1, 4, 6-trisubstituted-2-alkyl-1H-benzo[d]imidazole derivatives as dihydroorotate oxygenase inhibitors | |
US20230192718A1 (en) | Bicyclic enone carboxylates as modulators of transporters and uses thereof | |
JP6283688B2 (en) | Novel pyrazole-substituted imidazopyrazine as casein kinase 1D / E inhibitor | |
JP2009506127A (en) | Anilinopyrazole derivatives useful for the treatment of diabetes | |
US9120780B2 (en) | Indole or indazole derivative or salt thereof | |
AU2015295380A1 (en) | Arylhydrazides containing a 2-pyridone moiety as selective antibacterial agents | |
US11192859B2 (en) | Quinoline compounds as modulators of RAGE activity and uses thereof | |
US20140038991A1 (en) | Protein Kinase Inhibitors | |
CA3230941A1 (en) | Ahr agonists | |
CN110662539A (en) | Method of using tri-substituted benzotriazole derivatives as dihydroorotate oxygenase inhibitors | |
CN111848605B (en) | Substituted pyrido [3,4-b ] pyrazin-2 (1H) -one compound, preparation method and application thereof | |
JP7110335B2 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
EA026330B1 (en) | New pyrimidine derivatives as phosphodiesterase 10 inhibitors (pde-10) | |
US20220281888A1 (en) | Bicyclic carboxylates as modulators of transporters and uses thereof | |
JP2024528729A (en) | SRPK inhibitors | |
BR112017025356B1 (en) | COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE FOR THE MANUFACTURE OF A MEDICINE |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: NIROGYONE THERAPEUTICS, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SANDANAYAKA, VINCENT;WU, QIONG;REEL/FRAME:042398/0671 Effective date: 20151116 |
|
FEPP | Fee payment procedure |
Free format text: ENTITY STATUS SET TO SMALL (ORIGINAL EVENT CODE: SMAL); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: FINAL REJECTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: ADVISORY ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: FINAL REJECTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT RECEIVED |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
AS | Assignment |
Owner name: NIROGY THERAPEUTICS, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NIROGYONE THERAPEUTICS, INC.;REEL/FRAME:054869/0528 Effective date: 20200922 |
|
FEPP | Fee payment procedure |
Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |